REVIEW URRENT C OPINION
T follicular helper cells and HIV/SIV-specific antibody responses Constantinos Petrovas and Richard A. Koup
Purpose of review Here, we describe recent data on the characterization of follicular helper CD4 T cells (Tfh) and the dynamics of Tfh–B-cell interactions in HIV and simian immunodeficiency virus (SIV) infection and discuss important aspects of these interactions that need to be addressed in order to design more effective vaccines that elicit broadly neutralizing antibodies. Recent findings Mouse, nonhuman primate (NHP) and human Tfh cells share phenotypic, functional and molecular programs, which are regulated by local signals and spatiotemporal parameters. Chronic HIV/SIV infection results in accumulation of Tfh, germinal center B cells and circulating virus-specific immunoglobulins in some individuals. However, most HIV/SIV-infected individuals do not mount broadly neutralizing antibodies, pointing to functional defects in Tfh cells in chronic HIV/SIV infection. The susceptibility of particular CD4 T-cell populations to HIV/SIV infection within lymph nodes notably impacts upon the dynamics of Tfh-germinal center B-cell interactions. Some circulating CD4 T cells share certain characteristics with Tfh cells, however, their direct origin from germinal center Tfh cells is not clear. Summary There are many ways in which HIV and SIV influence the complex signals and mechanisms regulating the development of Tfh cells and their interactions with germinal center B cells. Understanding the biology of Tfh cells will be necessary to appropriately recruit these cells during vaccination with the goal of stimulating a more broad and potent neutralizing antibody response. Keywords antibodies, HIV, simian immunodeficiency virus, T follicular helper cells
INTRODUCTION Despite over two decades of research, the goal of developing an effective vaccine for HIV has not been achieved. The recent failure of vaccines designed to elicit primarily CD8 T-cell responses has refocused efforts on designing vaccines that will stimulate neutralizing antibodies [1,2]. The broadly neutralizing antibodies, which have been isolated from several HIV-infected individuals, are all characterized by a high degree of somatic hypermutation [3–5], indicating that extensive affinity maturation within germinal centers will be required in order to recapitulate these antibody responses through vaccination. Specialized CD4 T cells called T follicular helper cells (Tfh) traffic to the germinal centers and help regulate the process of somatic hypermutation in germinal center B cells. It is, therefore, important to understand the role of these T cells in the generation of broad neutralizing antibodies during HIV infection, and how they can be
specifically targeted through vaccination. Here, we review the recent published data on the dynamics of Tfh cells during HIV and simian immunodeficiency virus (SIV) infection and discuss important questions that need to be addressed in order to design more effective vaccines targeting the humoral arm of the adaptive immune system.
LESSONS FROM MOUSE MODELS Recent studies in mice have revealed the fundamental role of Tfh cells, a highly specialized CD4 T-cell Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA Correspondence to Richard A. Koup, MD, Vaccine Research Center, NIAID, NIH, 40 Convent Drive, Bethesda, MD 20892, USA. Tel: +1 301 594 8574; fax: +1 301 480 2779; e-mail: [email protected] Curr Opin HIV AIDS 2014, 9:235–241 DOI:10.1097/COH.0000000000000053
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KEY POINTS Tfh cells are key players in the development of HIV/SIVspecific B-cell responses. HIV/SIV can adversely affect the dynamics of Tfh cells and their interaction with germinal center B cells in many ways. Manipulation of Tfh cells could be important for strategies that seek to elicit broadly neutralizing antibodies.
population within germinal centers, in the maturation of B cells and the generation of effective pathogen-specific humoral responses [6–9]. Mouse Tfh cells express the surface receptors chemokine C-X-C motif receptor 5 (CXCR5), programmed cell death-1 (PD-1) and inducible T-cell costimulator (ICOS) [6,10–12], and their frequency, function and localization are influenced by the availability of antigen [10,13,14], chemokines [chemokine C-X-C motif ligand 13 (CXCL13 and stromal cellderived factor 1 (SDF-1)] [15] and the expression of receptors, including ICOS [16] and signaling lymphocytic activation molecule (SLAM)-family members [17,18]. It has been suggested that Tfh cells can arise from Th1 [19], Th2 [20] or other CD4 T-cell lineages [21]. Although these studies imply a plasticity of the in-vivo origin of Tfh cells when compared with other lineages, it is well established that expression of Bcl-6 [12] in combination with the function of soluble factors, such as interleukin 6 (IL-6) [22], is central to the lineage commitment of Tfh cells. In contrast, much less information is known about the fate of Tfh cells both after clearance of an acute infection and during chronic infection. It has been proposed that Tfh cells can revert to a central memory phenotype or undergo cell death after the effector phase of a specific immune response [23]. Furthermore, the ability of memory Tfh to traffic within the lymph nodes [24] or to peripheral tissues [25] further complicates our ability to understand the generation and fate of memory Tfh cells. The role of signal-transducer and activator of transcriptions (STATs) in the development of Tfh cells is now well established with STAT3 activation supporting their differentiation [7,21] and STAT5 activation favoring the development on non-Tfh lineages [26,27]. Recent studies have shown that STAT1, a major inducer of Th1 CD4 T cells [28] could support Tfh-cell development at very early stages of their differentiation [29 ]. Therefore, the relative phosphorylation status of STAT1, -3 and -5 &
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could serve as a biological marker when studying the dynamics of Tfh cells. Antigen-specific B cells must interact with Tfh cells in the germinal center [6,8] in order for activation, differentiation, isotype switching and selection of high-affinity memory B cells and plasma cells [13] to occur; a process in which the costimulatory molecules PD-1, ICOS and CD40-ligand (CD40) and soluble factors IL-4, IL-10 and IL-21 are involved [6,10,30]. Tfh cells are also reciprocally regulated through their interaction with germinal center B cells, specifically through ICOS/ICOSligand (ICOS-L) and CD40/CD40L interactions, soluble factors (IL-21 and IL-6) and B-cell-expressed CD80 [31 ,32,33]. To further add to this complexity, recent studies have shown that spatiotemporal factors greatly impact upon Tfh–B-cell interactions [34,35] so where and when the interactions occur may be at least as important as the cytokine and costimulatory molecules mediating these interactions. &
CHARACTERIZATION OF T FOLLICULAR HELPER CELLS IN HUMANS Human Tfh cells were first described in early 2000 based on their ability to deliver in-vitro help to autologous B cells [36]. Subsequent studies have described the unique molecular signature of human Tfh cells expressing CD57 and chemokine C-X-C motif receptor 5 (CXCR5) [37,38]. Phenotypic analysis of human Tfh cells revealed a conserved phenotype in humans, nonhuman primates (NHPs) and mice [6,38,39 ]. Similar to mice, human Tfh cells have a gene expression profile distinct from that of Th1 or Th2 cells [37,38]. Phenotypically, Tfh cells are characterized by high expression of CXCR5, CXCR4, CD95, CD154, BTLA, ICOS and CD69 [40]. Functionally, Tfh cells are capable of producing IL-21 and IL-4 but are compromised in their ability to secrete Th1 and Th2 cytokines [30,39 ]. A subpopulation of CXCR5high Tfh cells that expresses CD57 (germinal center Tfh) produces CXCL-13, the ligand of CXCR5 [38]. In addition, a Tfh-cell population that can produce IL-10, a cytokine characteristic of Treg cells [43], has been described [39 ,41,42]. This population, however, does not express other typical T regulatory-cell markers CD25þFoxP3þ [39 ,44] calling into question its actual lineage commitment. Similar to mouse Tfh cells, the transcriptional factors Bcl-6 and Maf are critical for human Tfh-cell-development [45]. Furthermore, activation of STAT3 is critical in the differentiation of human Tfh [46 ]. Collectively, these studies point to the fact that conserved mechanisms regulate Tfh cells in mice and humans. &&
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DYNAMICS OF T FOLLICULAR HELPER CELLS IN HIV AND SIMIAN IMMUNODEFICIENCY VIRUS INFECTION
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The chronic phase of HIV infection is characterized by major changes in the constitution of the lymph node microenvironment, including fibrosis, depletion of follicular reticulum cells [47] and shifts in CD4 T-cell and B-cell populations [48 ,49 ]. Despite overall loss of CD4 T cells during HIV infection, PD-1highCXCR5high Tfh cells accumulate in some infected individuals [48 ,49 ]. These cells were characterized by increased expression of Bcl-6 [48 ] and secretion of IL-21 [48 ,49 ]. Interestingly, the frequency of HIV Env-specific Tfh cells was significantly less than that of Gag-specific Tfh cells [48 ,49 ]. Whether these dynamics represent a preferential generation of Gag-specific Tfh cells or increased loss of Env-specific CD4 T cells, especially in the presence of abundant HIV virions within the germinal center [50,51] is not clear. Suppressing viral replication with antiretroviral treatment (ART) led to a reduction in the frequency of Tfh cells [48 ,49 ]. Despite the increased frequency of Tfh cells, most HIV-infected individuals are not capable of mounting broadly neutralizing antibodies, suggesting that Tfh cells in chronic HIV infection may be functionally impaired. Indeed, a defect in PD-1/PD-L1 interaction leading to Tfh-cell impairment in HIV infection as a mechanism responsible for the impaired function of Tfh cells &
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in HIV was recently described [52 ]. Specifically, it was proposed that the highly expressed PD-L1 on germinal center B cells could negatively regulate the function of Tfh cells through interaction with PD-1 [52 ]. The unusually high expression of PD-1 on Tfh cells compared with other CD4 T-cell populations could facilitate the selective delivery of negative signals to Tfh cells impairing their function or even their survival [53]. The dynamics of CD4 T-cell populations in NHP in the absence or presence of SIV infection have recently been described [35,39 ,54]. NHP Tfh cells have a phenotype (CCR7low, CD127low, PD-1high, ICOShigh, CTLA-4high, CD95high, BTLAhigh and Bcl-6high), localization and capacity for in-vitro B-cell help that is similar to what has been described in humans and mice [39 ]. SIV infection has a direct effect on NHP Tfh cells, specifically altering their molecular profile [39 ]. Similar to what is described during chronic HIV infection, NHP Tfh cells expand, at least in some of the animals, during chronic SIV infection, and this change is associated with higher titers of SIV-specific antibodies (described in more detail in the next section) [39 ] (Fig. 1). Finally, despite their activation status, the in-vivo cycling capacity of NHP Tfh cells is compromised compared with other CD4 T-cell populations within the lymph node [39 ]. Because of these similarities with HIV infection in humans, SIV infection of NHP Tfh cells can be used to study the effects of chronic lentivirus &&
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FIGURE 1. Major events related to the dynamics of Tfh cells in HIV/SIV infection are depicted. Acute infection is characterized by a balanced phosphorylation/activation of STAT1 (an inducer of Th1 cell type) and STAT3 (an inducer of Tfh cell type). The increased susceptibility of GC Tfh cells to SIV infection suggests that infection per se may play an important role in the dynamics of Tfh cells during acute HIV/SIV. During the chronic infection, accumulation of Tfh cells is associated with increased immune activation while no preferential infection of Tfh compared with non-Tfh cells was observed. An increased expression of the IL-6/IL-6R axis, however, is accompanied by an impaired phosphorylation/activation of STAT1. These cellular interactions are associated with dramatic changes in Tfh-cell biology (increased expression of IFN-g- and TGF-b-related genes) and increased production of virus-specific immunoglobulin. Therefore, biological interactions, beyond the infection of CD4 T cells per se, play a critical role for the dynamics of Tfh cells during chronic HIV/SIV infection. GC, germinal center; IFN-g, interferon gamma; IL-6, interleukin 6; SIV, simian immunodeficiency virus; STAT1, signal-transducer and activator of transcription 1; Tfh, T follicular helper cells; TGF-b, transforming growth factor beta. 1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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infections on Tfh cells in vivo. One slight problem is that CD57 identifies a Tfh-cell population localized within the germinal center [41], but this marker is not available for NHP studies. However, low expression of CD150/SLAM appears to adequately identify NHP Tfh cells localized to the germinal center [39 ]. The regulation of Tfh- and Th1-cell differentiation in NHP appears to be controlled by IL6-dependent STAT1 versus STAT3 phosphorylation [39 ] (Fig. 1), similar to what has been described in mice and humans [7,46 ], further demonstrating the usefulness of the NHP system. Apart from the accumulation of NHP Tfh cells [35,39 ], chronic SIV infection dramatically changed the overall quality of germinal center Tfh cells [39 ]. Specifically, chronic SIV infection was associated with an upregulation of the interferongamma (IFN-g)-induced genes in germinal center Tfh cells indicating an increased response to the elevated levels of IFN-g found in chronic SIV, an upregulation of transforming growth factor beta (TGF-b)-associated genes suggesting a role of TGF-b as a regulator of germinal center Tfh-cell dysfunction in SIV-infected NHPs and a significant reduction in the expression of the IL4 gene in germinal center Tfh cells from SIV-infected NHPs [39 ]; a cytokine with a critical role in memory B cell survival and isotype switching [55]. The dynamics of CD4 T cells within the lymphoid organs during the HIV and SIV infection appear to result from both an altered differentiation process and the susceptibility of particular CD4 T-cell populations to infection and cell death. Early studies revealed that CD4 T cells in LN are a major source for HIV infection and spreading of HIV [56,57] with follicular dendritic cells playing an important role in capturing and presenting HIV to the CD4 T cells [50,51]. In addition, germinal center CD4 T cells (defined by CD57) show a significantly higher frequency of HIV infection compared with extrafollicular CD4 T cells [58]. A significantly increased frequency of HIV DNA was recently demonstrated in CXCR5highPD-1high Tfh cells compared with non-Tfh cells from HIVþ lymph nodes [49 ]. Furthermore, Tfh cells are exquisitely capable of supporting in-vitro HIV replication [49 ] suggesting that Tfh could serve as a major site for HIV infection and replication in vivo. The picture in SIV infection is still somewhat unclear. In one study, SIV DNA was increased in Tfh cells (as compared with other LN CD4 T cells) only during acute infection [39 ]. A more recent study, however, found that the higher SIV RNA content in Tfh cells extended into chronic SIV infection, suggesting more active viral replication in these cells throughout SIV infection [59]. Collectively, these studies demonstrate that Tfh &&
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cells are at least one CD4 T-cell population in LNs that actively replicate HIV/SIV, and, depending upon their fate, could be a potential source of latently infected cells. Further understanding the stimulation, survival, signaling and transcriptional regulation of non-Tfh and Tfh cells will be a prerequisite to understanding their dynamics in chronic HIV/SIV infection and their potential role in the establishment of latency within lymphoid organs. In addition, local signals, such as the production of IL-10 by particular follicular CD4 T cells, may prove critical for our understanding of the role of immunosuppressive pathways in HIV/SIV pathogenesis and vaccine development.
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DYNAMICS OF T FOLLICULAR HELPER–BCELL INTERACTION IN CHRONIC HIV/ SIMIAN IMMUNODEFICIENCY VIRUS &
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Accumulation of Tfh cells in chronic HIV [48 ,49 ] and SIV [35,39 ] infection is associated with expansion of germinal center B cells [35,39 ,48 ,49 ]. Specifically, there is a significant correlation between the frequency of Tfh and germinal center B cells in chronically HIV-infected donors on and off ART [49 ]. This orchestrated accumulation of Tfh and germinal center B cells was accompanied by hypergammaglobulinemia in both chronic HIV [48 ] and SIV [35,39 ] infection. Furthermore, both the titers as well as the avidity of circulating SIVspecific immunoglobulins were higher in NHPs in which there was evidence of Tfh-cell accumulation [39 ]. These data point to cooperation between the Tfh and germinal center B-cell responses within the germinal center during chronic HIV/SIV infection consistent with the hypothesis that these two populations are reciprocally regulated [31 ,32,33]. However, certain functional alterations imparted by SIV upon the Tfh cells (i.e. reduction of IL4) [39 ] do not adversely affect the ability of B cells to respond to SIV. Therefore, upregulation of alternative signals affecting the development of B cells could counteract the functional impairment of Tfh cells. Presumably, the development of broadly neutralizing antibodies to SIV or HIV requires stringent regulation of germinal center B-cell development wherein many factors may be important including, but not limited to, the availability and sequence evolution of HIV/SIV envelope [60 ], the receptor expression on, the dynamic interactions between Tfh and germinal center B cells and the relative kinetics of B-cell transit between dark and light zones of the germinal center [24,61]. Therefore, there are many ways in which HIV and SIV may adversely impact upon the complex signals and mechanisms required for further affinity maturation of germinal center B-cell &&
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Tfh and HIV-specific B-cell responses Petrovas and Koup
responses during these chronic infections. To better understand how the process of Tfh- and B-cell interactions is affected by HIV and SIV infection, and how these affect the generation of neutralizing antibodies, there are several things that will need to be further investigated. It will be important to define the role of general immune activation compared with antigen-specific stimulation in this process. This is particularly important in chronic infection wherein an altered cytokine milieu coexists with an abnormal tissue structure and ongoing virus replication and evolution. In addition, we need a better understanding of how the altered dynamics of CD4 T-cell differentiation in chronic HIV/SIV infection impact the development of B-cell responses at different stages of affinity maturation. Specifically, are particular B-cell clones selected early on [62] leading to their premature expansion, survival and differentiation within the germinal center? Do any of these mechanisms explain why an increased frequency of Tfh and B cells does not necessarily lead to faster development of broadly neutralizing antibodies? Finally, the role of particular costimulatory/coinhibitory networks (receptors and soluble factors) in the reciprocal regulation of Tfh and germinal center-B cells needs to be better understood.
ARE MEMORY T FOLLICULAR HELPER CELLS PRESENT IN THE PERIPHERAL BLOOD? The fate of memory Tfh cells is unclear. The identification of circulating CD4 T-cell populations that could represent part of the memory Tfh pool has been the focus of recent studies [63,64 ,65 ,66 , 67–69]. Several markers, including CXCR5, CXCR3, chemokine C-C motif receptor 6 (CCR6), PD-1, ICOS, IL-21 and IFN-g have been used for the identification of peripheral Tfh (pTfh). Although there is a consensus that pTfh expresses CXCR5 and PD-1 [63,64 ,65 ,66 ,68,69], the differentiation stage of the CD4 T cell compartment in these studies, defined by CD27 and CD45RO [64 ,66 ,68] CD45RA [63,65 ,67], CCR7 [64 ,65 ,66 ], CCR6 and CXCR3 [64 ,65 ,66 ] is not consistent. Given the high heterogeneity of circulating CD4 T cells, this discrepancy has significant impact on the definition of pTfh and the perceived biology of these populations. To further add to this complexity, recent studies have shown that ‘memory Tfh’ are not characterized by a typical ‘effector Tfh’ phenotype [70] with the latter being able to traffic between germinal centers within lymphoid tissues [24]. In line with this, it has been proposed that the pTfh cells may represent a pre-Tfh population generated &
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before the germinal center [64 ,65 ] rather than a remnant of a germinal center Tfh population [66 ]. Although at low levels, the capacity for IL-21 production by pTfh cells is a common finding in these studies [63,64 ,65 , 66 ,68,69]. However, IL-2 and IFN-g production were more prominent in pTfh cells in some of these studies [64 ,65 ] adding to the lack of clear origin of these phenotypically defined populations. Central to these studies is the identification of particular CD4 T-cell populations with increased ability to support the isotype switching of autologous B cells in an in-vitro coculture system [63,64 ,65 ,66 , 67,68]. Still, the nature of the B cells used as a starting material is not consistent with some studies using naive [63,64 ,67], memory [63,65 ,66 ] or even total [68,69] B cells in their coculture system. Given the differences in the activation, proliferation and survival of these B-cell subsets, the choice of the starting B-cell population could significantly impact the outcome of the particular experiments and the assignment of Tfh phenotype to a particular CD4 T-cell population. Furthermore, whether or not the described pTfh cells are associated with a better neutralizing activity is not clear [64 ,66 ]. The differences in pTfh-cell definition, the characteristics of the study cohorts and the time points sampled could all contribute to this discrepancy. Given the importance of B-cell responses for the development of an effective vaccine against HIV, there is an increasing interest in identifying immune correlates associated with the quality of B-cell responses in the context of HIV/SIV infection or monitoring of vaccine-induced responses. The recent studies, however, point to the need for a consensus on the definition of pTfh cells and the assays used for in-vitro B-cell help. Furthermore, more studies are needed to clarify whether pTfh cells are a valid surrogate for true Tfh cells or a predictor of neutralizing antibody activity in HIV/ SIV infection or vaccination. &&
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CONCLUSION Accumulating data show the critical role of Tfh cells in regulating the development of antigen-specific B cells. HIV/SIV infection induces multiple changes in Tfh-cell numbers and function, ultimately affecting the development of HIV/SIV-specific antibodies. Future studies are needed to delineate the regulation of Tfh cells that could inform vaccination strategies with the goal of eliciting broad neutralizing antibody responses. Acknowledgements This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National
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Institutes of Health and CAVD grant #OPP1032325 from the Bill and Melinda Gates Foundation. Conflicts of interest The authors declare no competing financial interests.
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This is the first study describing the phenotype, localization, function and molecular gene profile of Tfh cells in SIV infection. Potential mechanisms regulating the dynamics of Tfh cells in chronic SIV infection are also shown. 40. Ma CS, Suryani S, Avery DT, et al. Early commitment of naive human CD4þ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol Cell Biol 2009; 87:590–600. 41. Kim CH, Rott LS, Clark-Lewis I, et al. Subspecialization of CXCR5þ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5þ T cells. J Exp Med 2001; 193:1373–1381. 42. Linterman MA, Pierson W, Lee SK, et al. Foxp3þ follicular regulatory T cells control the germinal center response. Nat Med 2011; 17:975–982. 43. Fujio K, Okamura T, Yamamoto K. The family of IL-10-secreting CD4þ T cells. Adv Immunol 2010; 105:99–130. 44. Marinova E, Han S, Zheng B. Germinal center helper T cells are dual functional regulatory cells with suppressive activity to conventional CD4þ T cells. J Immunol 2007; 178:5010–5017. 45. Kroenke MA, Eto D, Locci M, et al. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol 2012; 188:3734– 3744. 46. Ma CS, Avery DT, Chan A, et al. Functional STAT3 deficiency compromises & the generation of human T follicular helper cells. Blood 2012; 119:3997– 4008. This study describes the defective generation of Tfh cells in human donors with STAT3 deficiency and further highlights the importance of this transcription factor in the differentiation of CD4 T cells toward Tfh. 47. Zeng M, Smith AJ, Wietgrefe SW, et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest 2011; 121:998–1008. 48. Lindqvist M, van Lunzen J, Soghoian DZ, et al. Expansion of HIV-specific T & follicular helper cells in chronic HIV infection. J Clin Invest 2012; 122:3271– 3280. This is the first study describing the dynamics of HIV-specific Tfh cells in chronic HIV infection. The study shows an accumulation of Tfh cells in untreated chronic HIV, which is associated with hypergammaglobulinemia. A preferential accumulation of Gag- over Env-specific Tfh cells is also shown. 49. Perreau M, Savoye AL, De Crignis E, et al. Follicular helper T cells serve as the && major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med 2013; 210:143–156. This study provides evidence that Tfh cells are a major site for HIV infection. The described data point to Tfh as an important pool of latently-infected cells and further highlights their importance in development of ‘cure’ strategies.
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Tfh and HIV-specific B-cell responses Petrovas and Koup 50. Schmitz J, van Lunzen J, Tenner-Racz K, et al. Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia. J Immunol 1994; 153: 1352–1359. 51. Smith-Franklin BA, Keele BF, Tew JG, et al. Follicular dendritic cells and the persistence of HIV infectivity: the role of antibodies and Fcgamma receptors. J Immunol 2002; 168:2408–2414. 52. Cubas RA, Mudd JC, Savoye AL, et al. Inadequate T follicular cell help impairs && B cell immunity during HIV infection. Nat Med 2013; 19:494–499. This paper describes the first study describing a mechanism of selective depletion of virus-specific Tfh cells in lymph nodes from HIV-infected individuals. The study provides evidence that this process is mediated by an augmented interaction between PD-1 on virus-specific Tfh cells and PD-L1 expressed on germinal center B cells. 53. Good-Jacobson KL, Szumilas CG, Chen L, et al. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 2010; 11:535–542. 54. Onabajo OO, George J, Lewis MG, et al. Rhesus macaque lymph node PD-1hiCD4þ T cells express high levels of CXCR5 and IL-21 and display a CCR7lowICOSþBcl6þ T-follicular helper (Tfh) cell phenotype. PLoS One 2013; 8:e59758. 55. Paul WE, Ohara J. B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol 1987; 5:429–459. 56. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362:359–362. 57. Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362:355–358. 58. Hufert FT, van Lunzen J, Janossy G, et al. Germinal centre CD4þ T cells are an important site of HIV replication in vivo. AIDS 1997; 11:849–857. 59. Xu Y, Weatherall C, Bailey M, et al. Simian immunodeficiency virus infects follicular helper CD4 T cells in lymphoid tissues during pathogenic infection of pigtail macaques. J Virol 2013; 87:3760–3773. 60. Liao HX, Lynch R, Zhou T, et al. Co-evolution of a broadly neutralizing HIV-1 && antibody and founder virus. Nature 2013; 496:469–476. This paper describes an important study describing the concomitant evolution of HIV and antibody neutralization breadth with major implication for the design of vaccines to elicit neutralizing antibodies. 61. Victora GD, Schwickert TA, Fooksman DR, et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 2010; 143:592–605.
62. Schwickert TA, Victora GD, Fooksman DR, et al. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J Exp Med 2011; 208:1243–1252. 63. Bentebibel SE, Lopez S, Obermoser G, et al. Induction of ICOSþCXCR3þ CXCR5þ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med 2013; 5:176ra32. 64. Boswell KL, Paris P, Boritz E, et al. Loss of circulating CD4 T cells with B cell & helper function during chronic HIV infection. PLoS Pathog 2014; 10:e1003853. This study investigates the in-vitro B-cell helper activity of circulating CD4 T-cell populations. The authors provide data on the phenotype, function and frequency of circulating Tfh cells in healthy and HIV-infected individuals. The data indicate that peripheral Tfh cells may originate from a nongerminal center Tfh population. 65. He J, Tsai LM, Leong YA, et al. Circulating precursor CCR7loPD-1hi CXCR5þ && CD4þ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 2013; 39:770–781. This study describes the phenotype and function of circulating CD4 T cells with Tfh characteristics. The study provides evidence that this circulating population originates from a nongerminal center pre-Tfh population. 66. Locci M, Havenar-Daughton C, Landais E, et al. Human circulating && PD-1þCXCR3CXCR5þ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 2013; 39:758– 769. This study describes the phenotype, function and gene profile of a circulating CD4 T cell population sharing Tfh features. The authors provide data showing a positive correlation between the frequency of this population and the levels of broadly neutralizing antibodies against HIV, indicating that this frequency could be used as a correlate for the evaluation of vaccine strategies. 67. Morita R, Schmitt N, Bentebibel SE, et al. Human blood CXCR5þCD4þ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011; 34:108–121. 68. Pallikkuth S, Parmigiani A, Silva SY, et al. Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine. Blood 2012; 120:985–993. 69. Spensieri F, Borgogni E, Zedda L, et al. Human circulating influenza-CD4þ ICOS1þIL-21þ T cells expand after vaccination, exert helper function, and predict antibody responses. Proc Natl Acad Sci U S A 2013; 110:14330– 14335. 70. Hale JS, Youngblood B, Latner DR, et al. Distinct memory CD4þ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity 2013; 38:805–817.
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T follicular helper cells and HIV/SIV-specific antibody responses Constantinos Petrovas and Richard A. Koup
Purpose of review Here, we describe recent data on the characterization of follicular helper CD4 T cells (Tfh) and the dynamics of Tfh–B-cell interactions in HIV and simian immunodeficiency virus (SIV) infection and discuss important aspects of these interactions that need to be addressed in order to design more effective vaccines that elicit broadly neutralizing antibodies. Recent findings Mouse, nonhuman primate (NHP) and human Tfh cells share phenotypic, functional and molecular programs, which are regulated by local signals and spatiotemporal parameters. Chronic HIV/SIV infection results in accumulation of Tfh, germinal center B cells and circulating virus-specific immunoglobulins in some individuals. However, most HIV/SIV-infected individuals do not mount broadly neutralizing antibodies, pointing to functional defects in Tfh cells in chronic HIV/SIV infection. The susceptibility of particular CD4 T-cell populations to HIV/SIV infection within lymph nodes notably impacts upon the dynamics of Tfh-germinal center B-cell interactions. Some circulating CD4 T cells share certain characteristics with Tfh cells, however, their direct origin from germinal center Tfh cells is not clear. Summary There are many ways in which HIV and SIV influence the complex signals and mechanisms regulating the development of Tfh cells and their interactions with germinal center B cells. Understanding the biology of Tfh cells will be necessary to appropriately recruit these cells during vaccination with the goal of stimulating a more broad and potent neutralizing antibody response. Keywords antibodies, HIV, simian immunodeficiency virus, T follicular helper cells
INTRODUCTION Despite over two decades of research, the goal of developing an effective vaccine for HIV has not been achieved. The recent failure of vaccines designed to elicit primarily CD8 T-cell responses has refocused efforts on designing vaccines that will stimulate neutralizing antibodies [1,2]. The broadly neutralizing antibodies, which have been isolated from several HIV-infected individuals, are all characterized by a high degree of somatic hypermutation [3–5], indicating that extensive affinity maturation within germinal centers will be required in order to recapitulate these antibody responses through vaccination. Specialized CD4 T cells called T follicular helper cells (Tfh) traffic to the germinal centers and help regulate the process of somatic hypermutation in germinal center B cells. It is, therefore, important to understand the role of these T cells in the generation of broad neutralizing antibodies during HIV infection, and how they can be
specifically targeted through vaccination. Here, we review the recent published data on the dynamics of Tfh cells during HIV and simian immunodeficiency virus (SIV) infection and discuss important questions that need to be addressed in order to design more effective vaccines targeting the humoral arm of the adaptive immune system.
LESSONS FROM MOUSE MODELS Recent studies in mice have revealed the fundamental role of Tfh cells, a highly specialized CD4 T-cell Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA Correspondence to Richard A. Koup, MD, Vaccine Research Center, NIAID, NIH, 40 Convent Drive, Bethesda, MD 20892, USA. Tel: +1 301 594 8574; fax: +1 301 480 2779; e-mail: [email protected] Curr Opin HIV AIDS 2014, 9:235–241 DOI:10.1097/COH.0000000000000053
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KEY POINTS Tfh cells are key players in the development of HIV/SIVspecific B-cell responses. HIV/SIV can adversely affect the dynamics of Tfh cells and their interaction with germinal center B cells in many ways. Manipulation of Tfh cells could be important for strategies that seek to elicit broadly neutralizing antibodies.
population within germinal centers, in the maturation of B cells and the generation of effective pathogen-specific humoral responses [6–9]. Mouse Tfh cells express the surface receptors chemokine C-X-C motif receptor 5 (CXCR5), programmed cell death-1 (PD-1) and inducible T-cell costimulator (ICOS) [6,10–12], and their frequency, function and localization are influenced by the availability of antigen [10,13,14], chemokines [chemokine C-X-C motif ligand 13 (CXCL13 and stromal cellderived factor 1 (SDF-1)] [15] and the expression of receptors, including ICOS [16] and signaling lymphocytic activation molecule (SLAM)-family members [17,18]. It has been suggested that Tfh cells can arise from Th1 [19], Th2 [20] or other CD4 T-cell lineages [21]. Although these studies imply a plasticity of the in-vivo origin of Tfh cells when compared with other lineages, it is well established that expression of Bcl-6 [12] in combination with the function of soluble factors, such as interleukin 6 (IL-6) [22], is central to the lineage commitment of Tfh cells. In contrast, much less information is known about the fate of Tfh cells both after clearance of an acute infection and during chronic infection. It has been proposed that Tfh cells can revert to a central memory phenotype or undergo cell death after the effector phase of a specific immune response [23]. Furthermore, the ability of memory Tfh to traffic within the lymph nodes [24] or to peripheral tissues [25] further complicates our ability to understand the generation and fate of memory Tfh cells. The role of signal-transducer and activator of transcriptions (STATs) in the development of Tfh cells is now well established with STAT3 activation supporting their differentiation [7,21] and STAT5 activation favoring the development on non-Tfh lineages [26,27]. Recent studies have shown that STAT1, a major inducer of Th1 CD4 T cells [28] could support Tfh-cell development at very early stages of their differentiation [29 ]. Therefore, the relative phosphorylation status of STAT1, -3 and -5 &
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could serve as a biological marker when studying the dynamics of Tfh cells. Antigen-specific B cells must interact with Tfh cells in the germinal center [6,8] in order for activation, differentiation, isotype switching and selection of high-affinity memory B cells and plasma cells [13] to occur; a process in which the costimulatory molecules PD-1, ICOS and CD40-ligand (CD40) and soluble factors IL-4, IL-10 and IL-21 are involved [6,10,30]. Tfh cells are also reciprocally regulated through their interaction with germinal center B cells, specifically through ICOS/ICOSligand (ICOS-L) and CD40/CD40L interactions, soluble factors (IL-21 and IL-6) and B-cell-expressed CD80 [31 ,32,33]. To further add to this complexity, recent studies have shown that spatiotemporal factors greatly impact upon Tfh–B-cell interactions [34,35] so where and when the interactions occur may be at least as important as the cytokine and costimulatory molecules mediating these interactions. &
CHARACTERIZATION OF T FOLLICULAR HELPER CELLS IN HUMANS Human Tfh cells were first described in early 2000 based on their ability to deliver in-vitro help to autologous B cells [36]. Subsequent studies have described the unique molecular signature of human Tfh cells expressing CD57 and chemokine C-X-C motif receptor 5 (CXCR5) [37,38]. Phenotypic analysis of human Tfh cells revealed a conserved phenotype in humans, nonhuman primates (NHPs) and mice [6,38,39 ]. Similar to mice, human Tfh cells have a gene expression profile distinct from that of Th1 or Th2 cells [37,38]. Phenotypically, Tfh cells are characterized by high expression of CXCR5, CXCR4, CD95, CD154, BTLA, ICOS and CD69 [40]. Functionally, Tfh cells are capable of producing IL-21 and IL-4 but are compromised in their ability to secrete Th1 and Th2 cytokines [30,39 ]. A subpopulation of CXCR5high Tfh cells that expresses CD57 (germinal center Tfh) produces CXCL-13, the ligand of CXCR5 [38]. In addition, a Tfh-cell population that can produce IL-10, a cytokine characteristic of Treg cells [43], has been described [39 ,41,42]. This population, however, does not express other typical T regulatory-cell markers CD25þFoxP3þ [39 ,44] calling into question its actual lineage commitment. Similar to mouse Tfh cells, the transcriptional factors Bcl-6 and Maf are critical for human Tfh-cell-development [45]. Furthermore, activation of STAT3 is critical in the differentiation of human Tfh [46 ]. Collectively, these studies point to the fact that conserved mechanisms regulate Tfh cells in mice and humans. &&
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DYNAMICS OF T FOLLICULAR HELPER CELLS IN HIV AND SIMIAN IMMUNODEFICIENCY VIRUS INFECTION
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The chronic phase of HIV infection is characterized by major changes in the constitution of the lymph node microenvironment, including fibrosis, depletion of follicular reticulum cells [47] and shifts in CD4 T-cell and B-cell populations [48 ,49 ]. Despite overall loss of CD4 T cells during HIV infection, PD-1highCXCR5high Tfh cells accumulate in some infected individuals [48 ,49 ]. These cells were characterized by increased expression of Bcl-6 [48 ] and secretion of IL-21 [48 ,49 ]. Interestingly, the frequency of HIV Env-specific Tfh cells was significantly less than that of Gag-specific Tfh cells [48 ,49 ]. Whether these dynamics represent a preferential generation of Gag-specific Tfh cells or increased loss of Env-specific CD4 T cells, especially in the presence of abundant HIV virions within the germinal center [50,51] is not clear. Suppressing viral replication with antiretroviral treatment (ART) led to a reduction in the frequency of Tfh cells [48 ,49 ]. Despite the increased frequency of Tfh cells, most HIV-infected individuals are not capable of mounting broadly neutralizing antibodies, suggesting that Tfh cells in chronic HIV infection may be functionally impaired. Indeed, a defect in PD-1/PD-L1 interaction leading to Tfh-cell impairment in HIV infection as a mechanism responsible for the impaired function of Tfh cells &
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in HIV was recently described [52 ]. Specifically, it was proposed that the highly expressed PD-L1 on germinal center B cells could negatively regulate the function of Tfh cells through interaction with PD-1 [52 ]. The unusually high expression of PD-1 on Tfh cells compared with other CD4 T-cell populations could facilitate the selective delivery of negative signals to Tfh cells impairing their function or even their survival [53]. The dynamics of CD4 T-cell populations in NHP in the absence or presence of SIV infection have recently been described [35,39 ,54]. NHP Tfh cells have a phenotype (CCR7low, CD127low, PD-1high, ICOShigh, CTLA-4high, CD95high, BTLAhigh and Bcl-6high), localization and capacity for in-vitro B-cell help that is similar to what has been described in humans and mice [39 ]. SIV infection has a direct effect on NHP Tfh cells, specifically altering their molecular profile [39 ]. Similar to what is described during chronic HIV infection, NHP Tfh cells expand, at least in some of the animals, during chronic SIV infection, and this change is associated with higher titers of SIV-specific antibodies (described in more detail in the next section) [39 ] (Fig. 1). Finally, despite their activation status, the in-vivo cycling capacity of NHP Tfh cells is compromised compared with other CD4 T-cell populations within the lymph node [39 ]. Because of these similarities with HIV infection in humans, SIV infection of NHP Tfh cells can be used to study the effects of chronic lentivirus &&
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FIGURE 1. Major events related to the dynamics of Tfh cells in HIV/SIV infection are depicted. Acute infection is characterized by a balanced phosphorylation/activation of STAT1 (an inducer of Th1 cell type) and STAT3 (an inducer of Tfh cell type). The increased susceptibility of GC Tfh cells to SIV infection suggests that infection per se may play an important role in the dynamics of Tfh cells during acute HIV/SIV. During the chronic infection, accumulation of Tfh cells is associated with increased immune activation while no preferential infection of Tfh compared with non-Tfh cells was observed. An increased expression of the IL-6/IL-6R axis, however, is accompanied by an impaired phosphorylation/activation of STAT1. These cellular interactions are associated with dramatic changes in Tfh-cell biology (increased expression of IFN-g- and TGF-b-related genes) and increased production of virus-specific immunoglobulin. Therefore, biological interactions, beyond the infection of CD4 T cells per se, play a critical role for the dynamics of Tfh cells during chronic HIV/SIV infection. GC, germinal center; IFN-g, interferon gamma; IL-6, interleukin 6; SIV, simian immunodeficiency virus; STAT1, signal-transducer and activator of transcription 1; Tfh, T follicular helper cells; TGF-b, transforming growth factor beta. 1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Spectrum of HIV antibodies in vaccine and disease
infections on Tfh cells in vivo. One slight problem is that CD57 identifies a Tfh-cell population localized within the germinal center [41], but this marker is not available for NHP studies. However, low expression of CD150/SLAM appears to adequately identify NHP Tfh cells localized to the germinal center [39 ]. The regulation of Tfh- and Th1-cell differentiation in NHP appears to be controlled by IL6-dependent STAT1 versus STAT3 phosphorylation [39 ] (Fig. 1), similar to what has been described in mice and humans [7,46 ], further demonstrating the usefulness of the NHP system. Apart from the accumulation of NHP Tfh cells [35,39 ], chronic SIV infection dramatically changed the overall quality of germinal center Tfh cells [39 ]. Specifically, chronic SIV infection was associated with an upregulation of the interferongamma (IFN-g)-induced genes in germinal center Tfh cells indicating an increased response to the elevated levels of IFN-g found in chronic SIV, an upregulation of transforming growth factor beta (TGF-b)-associated genes suggesting a role of TGF-b as a regulator of germinal center Tfh-cell dysfunction in SIV-infected NHPs and a significant reduction in the expression of the IL4 gene in germinal center Tfh cells from SIV-infected NHPs [39 ]; a cytokine with a critical role in memory B cell survival and isotype switching [55]. The dynamics of CD4 T cells within the lymphoid organs during the HIV and SIV infection appear to result from both an altered differentiation process and the susceptibility of particular CD4 T-cell populations to infection and cell death. Early studies revealed that CD4 T cells in LN are a major source for HIV infection and spreading of HIV [56,57] with follicular dendritic cells playing an important role in capturing and presenting HIV to the CD4 T cells [50,51]. In addition, germinal center CD4 T cells (defined by CD57) show a significantly higher frequency of HIV infection compared with extrafollicular CD4 T cells [58]. A significantly increased frequency of HIV DNA was recently demonstrated in CXCR5highPD-1high Tfh cells compared with non-Tfh cells from HIVþ lymph nodes [49 ]. Furthermore, Tfh cells are exquisitely capable of supporting in-vitro HIV replication [49 ] suggesting that Tfh could serve as a major site for HIV infection and replication in vivo. The picture in SIV infection is still somewhat unclear. In one study, SIV DNA was increased in Tfh cells (as compared with other LN CD4 T cells) only during acute infection [39 ]. A more recent study, however, found that the higher SIV RNA content in Tfh cells extended into chronic SIV infection, suggesting more active viral replication in these cells throughout SIV infection [59]. Collectively, these studies demonstrate that Tfh &&
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cells are at least one CD4 T-cell population in LNs that actively replicate HIV/SIV, and, depending upon their fate, could be a potential source of latently infected cells. Further understanding the stimulation, survival, signaling and transcriptional regulation of non-Tfh and Tfh cells will be a prerequisite to understanding their dynamics in chronic HIV/SIV infection and their potential role in the establishment of latency within lymphoid organs. In addition, local signals, such as the production of IL-10 by particular follicular CD4 T cells, may prove critical for our understanding of the role of immunosuppressive pathways in HIV/SIV pathogenesis and vaccine development.
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DYNAMICS OF T FOLLICULAR HELPER–BCELL INTERACTION IN CHRONIC HIV/ SIMIAN IMMUNODEFICIENCY VIRUS &
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Accumulation of Tfh cells in chronic HIV [48 ,49 ] and SIV [35,39 ] infection is associated with expansion of germinal center B cells [35,39 ,48 ,49 ]. Specifically, there is a significant correlation between the frequency of Tfh and germinal center B cells in chronically HIV-infected donors on and off ART [49 ]. This orchestrated accumulation of Tfh and germinal center B cells was accompanied by hypergammaglobulinemia in both chronic HIV [48 ] and SIV [35,39 ] infection. Furthermore, both the titers as well as the avidity of circulating SIVspecific immunoglobulins were higher in NHPs in which there was evidence of Tfh-cell accumulation [39 ]. These data point to cooperation between the Tfh and germinal center B-cell responses within the germinal center during chronic HIV/SIV infection consistent with the hypothesis that these two populations are reciprocally regulated [31 ,32,33]. However, certain functional alterations imparted by SIV upon the Tfh cells (i.e. reduction of IL4) [39 ] do not adversely affect the ability of B cells to respond to SIV. Therefore, upregulation of alternative signals affecting the development of B cells could counteract the functional impairment of Tfh cells. Presumably, the development of broadly neutralizing antibodies to SIV or HIV requires stringent regulation of germinal center B-cell development wherein many factors may be important including, but not limited to, the availability and sequence evolution of HIV/SIV envelope [60 ], the receptor expression on, the dynamic interactions between Tfh and germinal center B cells and the relative kinetics of B-cell transit between dark and light zones of the germinal center [24,61]. Therefore, there are many ways in which HIV and SIV may adversely impact upon the complex signals and mechanisms required for further affinity maturation of germinal center B-cell &&
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Tfh and HIV-specific B-cell responses Petrovas and Koup
responses during these chronic infections. To better understand how the process of Tfh- and B-cell interactions is affected by HIV and SIV infection, and how these affect the generation of neutralizing antibodies, there are several things that will need to be further investigated. It will be important to define the role of general immune activation compared with antigen-specific stimulation in this process. This is particularly important in chronic infection wherein an altered cytokine milieu coexists with an abnormal tissue structure and ongoing virus replication and evolution. In addition, we need a better understanding of how the altered dynamics of CD4 T-cell differentiation in chronic HIV/SIV infection impact the development of B-cell responses at different stages of affinity maturation. Specifically, are particular B-cell clones selected early on [62] leading to their premature expansion, survival and differentiation within the germinal center? Do any of these mechanisms explain why an increased frequency of Tfh and B cells does not necessarily lead to faster development of broadly neutralizing antibodies? Finally, the role of particular costimulatory/coinhibitory networks (receptors and soluble factors) in the reciprocal regulation of Tfh and germinal center-B cells needs to be better understood.
ARE MEMORY T FOLLICULAR HELPER CELLS PRESENT IN THE PERIPHERAL BLOOD? The fate of memory Tfh cells is unclear. The identification of circulating CD4 T-cell populations that could represent part of the memory Tfh pool has been the focus of recent studies [63,64 ,65 ,66 , 67–69]. Several markers, including CXCR5, CXCR3, chemokine C-C motif receptor 6 (CCR6), PD-1, ICOS, IL-21 and IFN-g have been used for the identification of peripheral Tfh (pTfh). Although there is a consensus that pTfh expresses CXCR5 and PD-1 [63,64 ,65 ,66 ,68,69], the differentiation stage of the CD4 T cell compartment in these studies, defined by CD27 and CD45RO [64 ,66 ,68] CD45RA [63,65 ,67], CCR7 [64 ,65 ,66 ], CCR6 and CXCR3 [64 ,65 ,66 ] is not consistent. Given the high heterogeneity of circulating CD4 T cells, this discrepancy has significant impact on the definition of pTfh and the perceived biology of these populations. To further add to this complexity, recent studies have shown that ‘memory Tfh’ are not characterized by a typical ‘effector Tfh’ phenotype [70] with the latter being able to traffic between germinal centers within lymphoid tissues [24]. In line with this, it has been proposed that the pTfh cells may represent a pre-Tfh population generated &
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before the germinal center [64 ,65 ] rather than a remnant of a germinal center Tfh population [66 ]. Although at low levels, the capacity for IL-21 production by pTfh cells is a common finding in these studies [63,64 ,65 , 66 ,68,69]. However, IL-2 and IFN-g production were more prominent in pTfh cells in some of these studies [64 ,65 ] adding to the lack of clear origin of these phenotypically defined populations. Central to these studies is the identification of particular CD4 T-cell populations with increased ability to support the isotype switching of autologous B cells in an in-vitro coculture system [63,64 ,65 ,66 , 67,68]. Still, the nature of the B cells used as a starting material is not consistent with some studies using naive [63,64 ,67], memory [63,65 ,66 ] or even total [68,69] B cells in their coculture system. Given the differences in the activation, proliferation and survival of these B-cell subsets, the choice of the starting B-cell population could significantly impact the outcome of the particular experiments and the assignment of Tfh phenotype to a particular CD4 T-cell population. Furthermore, whether or not the described pTfh cells are associated with a better neutralizing activity is not clear [64 ,66 ]. The differences in pTfh-cell definition, the characteristics of the study cohorts and the time points sampled could all contribute to this discrepancy. Given the importance of B-cell responses for the development of an effective vaccine against HIV, there is an increasing interest in identifying immune correlates associated with the quality of B-cell responses in the context of HIV/SIV infection or monitoring of vaccine-induced responses. The recent studies, however, point to the need for a consensus on the definition of pTfh cells and the assays used for in-vitro B-cell help. Furthermore, more studies are needed to clarify whether pTfh cells are a valid surrogate for true Tfh cells or a predictor of neutralizing antibody activity in HIV/ SIV infection or vaccination. &&
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CONCLUSION Accumulating data show the critical role of Tfh cells in regulating the development of antigen-specific B cells. HIV/SIV infection induces multiple changes in Tfh-cell numbers and function, ultimately affecting the development of HIV/SIV-specific antibodies. Future studies are needed to delineate the regulation of Tfh cells that could inform vaccination strategies with the goal of eliciting broad neutralizing antibody responses. Acknowledgements This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National
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Spectrum of HIV antibodies in vaccine and disease
Institutes of Health and CAVD grant #OPP1032325 from the Bill and Melinda Gates Foundation. Conflicts of interest The authors declare no competing financial interests.
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