Immunol Res DOI 10.1007/s12026-014-8530-3

IMMUNOLOGY AT THE UNIVERSITY OF IOWA

Peripheral regulation of T cells by dendritic cells during infection Emily A. Hemann • Kevin L. Legge

Kevin L. Legge

Ó Springer Science+Business Media New York 2014

Abstract It is well accepted that T cell responses are integral in providing protection during pathogenic infections. In numerous tissues, T cell responses are generated to combat infection. Typically, these T cell responses are primed in draining lymph nodes (LN) by dendritic cells (DC) that have migrated from the infected tissue. Previously, it was thought that after the initial encounter between DC and T cells in the LN, the T cells underwent a programmed response. However, it has become increasingly clear that direct interactions between DCs and T cells in infected, peripheral tissues can modulate the activation, effector function, tissue residence, and memory responses of these T cells. This review will highlight the contribution of local, direct DC: T cell interactions to the regulation of T cell responses in various tissues during inflammation and infection. Keywords

Dendritic cells  T cells  Regulation  Infection  Tissue immunity

Introduction The development of antigen-specific T cell responses is key in mediating protection against a number of bacterial and viral pathogens. According to the paradigm, T cell responses are primed in the lymph nodes (LN) and spleen by dendritic cells (DCs) that drain from the site of infection (reviewed in [1–3]). Tissue-resident DCs are constantly sampling the environment for pathogens. When a DC detects a pathogen within infected tissue, the DC matures and migrates to the regional draining LN. There, the activated, mature DC can interact with a naı¨ve T cell expressing a T cell receptor (TCR) recognizing the antigen being presented in the context of MHC,

E. A. Hemann  K. L. Legge Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA K. L. Legge (&) Department of Pathology, 1028ML, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA e-mail: [email protected]

along with appropriate costimulation and cytokines (reviewed in [4–7]). Following activation, the T cell begins to proliferate rapidly (undergoing expansion) and upregulate effector molecules, such as perforin/granzymes and cytokines. These effector T cells then migrate to the infected tissue to aid in clearance of the pathogen. Following clearance of the pathogen, a stable pool of memory T cells persists in the LNs, spleen and within the peripheral tissue, allowing for rapid clearance of subsequent, homologous (or very closely related) pathogens in the future. Previously, it was thought that the initial programming of the T cells in the LN was all that was necessary to drive effector function and tissue localization [8–10]. However, more recent work has demonstrated additional signals within the infected tissue provided by direct interactions with DCs regulate the development of both the effector and memory T cell responses (depicted in Fig. 1). In this review, we will discuss the contribution of direct DC interactions to the regulation of the following aspects of T cell immunity in the peripheral organs: (1) activation, (2) effector responses, and (3) localization and function of memory.

123

University of Iowa Immunology 2014

(c)

(a) Infected tissue

DC T cell

(b) LN

T cell

Fig. 1 Role of direct DC interactions in the regulation of T cell function. a DCs constantly survey tissues. b When a pathogen is detected by a DC, it matures and migrates to the tissue-draining LN where it can interact with naı¨ve T cells expressing a TCR specific for the antigen being presented by the DC in the context of MHC, along with appropriate costimulation and cytokines. Following activation, the T cells undergo expansion and upregulate effector molecules such as cytokines and perforin/granzymes. c These activated T cells then migrate to the infected tissue to aid in clearance of the pathogen. Recent work has demonstrated that subsequent direct interactions of DCs with T cells in infected tissue can regulate both the effector and memory functions of T cells. Additionally, in certain circumstances, DCs have been described to directly activate naı¨ve T cells within infected tissue to aid in pathogen clearance

Mucosal tissues Tertiary lymphoid structures have been described to arise in mucosal tissues such as the lung, intestine, and vagina in response to inflammation and infection in humans, as well as in a number of relevant animal models (reviewed in [11– 14]). These tertiary lymphoid structures are thought to serve as areas that facilitate local regulation of both CD4 and CD8 T cells by DCs (reviewed in [11–14]). Further, these lymphoid follicles within peripheral tissues have also been demonstrated to provide defined areas for antigen presentation outside of secondary lymphoid organs. Lung Inducible bronchus-associated lymphoid tissue (iBALT) has been demonstrated to appear in the lungs following repeated inflammation and/or IAV infection in humans and murine models [13, 15–19]. The maintenance of iBALT following IAV infection requires the presence of CD11c? DCs, as their depletion with diphtheria toxin (DT) in CD11c DT receptor transgenic mice 17 days following infection leads to a reduction of iBALT in the lungs [20].

123

Further, Moyron-Quiroz et al. [17] demonstrated that influenza-specific CD8 T cells can be primed and expand in the lungs of mice lacking LN, spleen, and Peyer’s patches (PP) when challenged with IAV. Importantly, these IAVspecific CD8 T cell responses primed within the lung were not only protective, but proved to be less pathogenic than anti-influenza immune responses generated in secondary lymphoid tissues [17]. This finding notably demonstrates DCs within the lungs are not only able to regulate existing CD8 effector populations within the lungs, but that they may also activate CD8 T cells within the lung environment that are potentially less detrimental to the host. During infection with influenza virus of hosts with a fully intact immune system, naı¨ve CD8 T cells are primed in the lung-draining LN and then migrate to the site of infection (i.e., lungs) in order to kill virally infected cells [21–25]. While the dLN is the initial site of expansion, activated CD8 T cells continue to proliferate in the lung during IAV infection [26]. This proliferation was correlated with increased migration of DCs to the lungs. Interestingly, studies from our laboratory have demonstrated that depletion of phagocytic cells from the airways following IAV infection leads to a blunting of the local, but not systemic, IAV-specific CD8 T cell response via apoptosis [27, 28]. This suggested a role for local DC: T cell interactions in maintaining the IAV-specific CD8 T cell response. In fact, local interactions of effector CD8 T cells with pDC or CD8a? DC are required in order to avoid apoptosis and develop a robust CD8 T cell response capable of efficiently clearing IAV [27, 28]. This peripheral DC: T cell interaction within the lungs of mice infected with IAV was found to be dependent on antigen presented in the context of MHC I and trans-presentation of IL-15 [27, 28]. The location of this interaction is currently under investigation, but studies from other groups have demonstrated that intratracheally transferred DCs migrate to iBALT where they subsequently interact with and activate CD8 T cells [29]. Therefore, it is possible iBALT provides an organized tertiary lymphoid structures/framework within the lungs where such DC: T cell interactions can occur. Following IAV infection, IAV-specific, long-lived memory CD8 T cells reside in the local lung tissue [8, 30– 37]. These local, tissue-resident memory cells are key in the early control of viral infection, as they are present at the initial site of antigen encounter and are able to rapidly respond following interaction with DCs to mediate protective immunity [32, 33, 38]. Importantly, tissue-resident IAV-specific memory T cells activated in the absence of secondary lymphoid organs are maintained long term within the tissue and expand upon secondary infection [39]. Therefore, DCs within the lungs are able to regulate activation of IAV-specific CD8 T cells along with modulating

University of Iowa Immunology 2014

effector and memory functions. While this section has focused on tissue-resident memory CD8 T cell populations, it should also be noted that memory, IAV-specific CD8 T cells that seed periphery (i.e., lungs) are also maintained within lung-draining LN following IAV infection via antigen-dependent interactions with migratory DCs [40]. Whether the contributions of DCs to T cell maintenance are as broad in the other tissues discussed throughout this review remains to be investigated. Intestine Gut-associated lymphoid tissues (GALT) within the intestines consist of PP and lymphocyte clusters present within the lamina propria (LP) [13]. DCs have been demonstrated to regulate tissue residence and memory reactivation of both CD4 and CD8 T cells within these areas, but only after priming of T cell responses has occurred in the LN [41–44]. While secondary lymphoid organs are required for the generation of pathogen-specific CD8 T cell responses in the LP following Listeria monocytogenes (LM) or vesicular stomatitis virus (VSV) infection, LM-specific memory CD8 T cell responses can be maintained in the absence of secondary lymphoid organs [44]. Studies have suggested that this interaction of intestinal T cells with gut-resident DCs is required to maintain tissue tropism and permit reactivation of T cells within the intestines [43]. Specifically, DCs resident within the intestines, and not LN-resident DCs transferred to the intestine, have been documented to be required for the establishment of CD8 T cell residence within the LP and GALT following inflammation through altering the expression of CD62L, a4b7, and CCR9 on the T cells [42, 43]. Furthermore, DCs from PP, but not the LN, were able to alter the expression of CD62L, a4b7, and CCR9 on CD8 T cells and lead to a tissue-resident phenotype [43]. While mucosal DC: CD8 T cell interactions have a clear role within the intestine during infection, the contribution of direct DC: T cell interactions in the regulation of intestinal CD4 T cell responses remains unclear. Mucosal DCs have been observed via microscopic methods to interact with CD4 T cells within the normal, uninfected intestinal LP, but it is unknown whether similar interactions occur during infection [41]. Further, while constant DC: CD4 T cell interactions within the intestines occur, whether these DCs are exerting tolerizing or potentially activating effects on CD4 T cells is not as well defined. In the future, it will also be important to determine which subsets of CD4 T cells are potentially regulated by direct interactions with DCs in the intestinal environment in the future.

Vagina While it has not been characterized as well as the other mucosal tissues discussed above, the vagina also gives rise to tertiary lymphoid structures known as genital-associated lymphoid tissues following simian immunodeficiency virus (SIV) and herpes simplex virus 2 (HSV-2) infection [45– 47]. Following infection of the genital tract with HSV-2, tissue-resident memory CD8 and CD4 T cell responses are generated that can be rapidly reactivated to produce IFNc to potentially aid in viral control and/or clearance upon reinfection [45, 47]. What role local DC: T cell interactions may contribute to regulation of CD4 and CD8 T cell responses in the vaginal mucosa remains unclear. However, CD11b?CD11c? APCs have been demonstrated to be required for IFNc production by type 1 helper CD4 T cells (Th1 cells) within the genital mucosa upon reinfection with HSV-2 [45].

Skin Skin-associated lymphoid tissues (SALT) have been proposed as a site for antigen presentation within the skin, highlighting the importance of the skin in immune responses in addition to its known role as a physical barrier [48–50]. Three major subsets of DCs have been described in the skin: CD103? DCs (Langerin? DCs), CD11b? DCs (Langerin- DCs/dermal DCs), and Langerhans cells [51– 54]. CD103? DCs are crucial in transport of antigen from the skin to the LN in order to generate pathogen-specific T cell responses [55]. However, what role, if any, CD103? DCs have in directly regulating T cell responses within the local skin environment remains understudied. In contrast, both CD11b? DCs and Langerhans cells have been shown to directly interact with T cells in the skin environment [54, 56–60]. The absence of CD11b? DCs impairs effector CD4 T cell responses during inflammation. Further, CD11b? dermal DCs directly regulate CD4 T cell responses in the skin by the presentation of peptide in the context of MHC I [56]. Specifically, the production of IFNc by Th1 cells while inhibiting CD4 regulatory T cell function locally in the inflamed skin within 12 h following peptide and adjuvant administration [56]. Langerhans cells have also been implicated in the regulation of tissue-resident memory CD4 and CD8 T cells within the skin in a manner that is dependent upon antigen presentation following infection with Candida albicans and HSV [57, 59]. These studies suggest constant antigen presentation by Langerhans cells within the skin may maintain tissue-resident memory T cell populations and allow for rapid recall responses upon reinfection.

123

University of Iowa Immunology 2014

Contrastingly, intraepithelial memory CD8 T cell populations have been described to persist long term within the skin environment and provide protection against subsequent local HSV infections in the absence of ongoing antigen presentation following their transfer directly into the skin [61]. While this study did not formally investigate a direct DC interaction in regulation of T cell responses in the skin during infection, and therefore, direct DC: T cell interactions cannot be ruled out, it suggests that in certain situations, DCs may not be required for the maintenance of tissue-resident CD8 T cells within the skin. These conflicting studies highlight the intriguing possibility that DCs may serve as a rheostat to balance effector and regulatory responses in the skin during and following infection, and that the requirement for DCs within the skin may vary depending upon the inflammation or infection present.

Liver Chronic infection of the liver with hepatitis C virus (HCV) results in the formation of ectopic lymphoid structures known as portal tract-associated lymphoid tissue (PALT) [62]. PALT structures contain germinal centers surrounded by a T cell zone. DCs are also found within PALT. While it has not been directly investigated, their presence within the PALT has led to the implication of DCs in regulation of liver ectopic lymphoid tissue development and organization [63, 64]. While we will only discuss the contribution DCs to hepatic regulation of T cell responses in this review, it should be noted that macrophages, hepatic stellate cells, and Kuppfer cells are also capable of antigen presentation that are present in the liver (reviewed in [65]). CD11c? monocytic DCs are recruited to areas of liver inflammation and co-localize with CD8 T cells during Propionibacterium acnes infection [64]. While these studies strongly suggested a role for DCs in hepatic CD8 T cell regulation, they did not demonstrate a specific function of DCs in local regulation of T cell responses, only colocalization. However, more recent work from Huang et al. [66] has determined that CD11cintCD11b? inflammatory DCs found proximal to CD8 T cells within the liver are directly responsible for the T cells proliferation in the liver tissue following chronic lymphocytic choriomeningitis (LCMV) or hepatitis B virus (HBV) infection. Blocking of the costimulatory molecules CD80, CD86, and OX40L on the surface of these inflammatory DCs prevents this proliferation [66]. Together, these studies indicate that direct interaction of DCs with T cells within the liver may be important in regulating responses during both acute and chronic infection. Interestingly, direct priming of HCV-specific CD8 T cell responses has also been described in humans following

123

liver transplantation [67]. HLA-A2-restricted, HCV-specific CD8 T cell responses were detected following transplant of an HLA-A2? liver into an HLA-A2- recipient. While it is clear that priming of CD8 T cells can occur in the liver, evidence suggests these CD8 T cells may be inferior in terms of their proliferative capacity and cytolytic function compared to their LN-primed counterparts [68]. Studies in murine systems have also demonstrated primary activation of cytotoxic CD8 T cells can occur in the liver following transplantation of livers into irradiated mice [69]. However, this study only investigated the induction of CD8 T cell responses following administration of the model antigen ovalbumin (OVA) in the context of inflammation rather than during natural infection. Therefore, in the future, it will be important to determine the specific contribution of liver- vs. LN-primed CD8 T cells in protection and progression to chronicity during liver infections. Further, understanding how local regulation of T cell responses in the liver by direct DC: T cell interactions leads to clearance of acute liver infection or progression to chronicity could aid in the development of therapeutic strategies to combat chronic hepatitis infections.

Brain/central nervous system Typically, the brain is not surveyed by lymphocytes and can be considered a somewhat immune-privileged organ [70]. However, viral infection of the brain has been demonstrated to induce long-lasting memory CD8 T cell populations [71]. Wakim et al. demonstrated that following VSV infection, tissue-resident memory CD8 T cells expressing CD103 (T cell resident memory [Trm]) persist within the brain. In order to determine whether these cells were primed within the brain or another organ, mice were seeded with OT-I cells (transgenic CD8 T cells specific for OVA antigen) and administered OVA-coated CD11c? DCs both intravenously and intracranially [71]. Intravenous DC administration did not induce the development of a Trm population within the brain. However, following intracranial injection of CD11c? DCs, OT-I Trm can be observed within the brain. Interactions between DCs and these T cells were directly observed within the brain 10 days following injection, highlighting the importance of local antigen presentation by DCs in generating and maintaining Trm populations. Other studies have also demonstrated that DCs are able to induce the activation of memory T cells in dorsal root ganglia during HSV latency, indicating DCs may be important in maintaining and regulating memory CD8 T cell responses throughout the central nervous system (CNS) [72]. The interactions between APCs and T cells within the CNS have also been documented to be detrimental in

University of Iowa Immunology 2014

certain circumstances [73]. DC: T cell interactions, which have been documented to increase the production of inflammatory cytokines and chemokines, and also upregulate metalloproteases. The increase in these molecules facilitated entry of T cells into the CNS, exacerbating disease. These seemingly conflicting findings within the brain/ CNS again highlight the potentially disparate roles of direct DC interactions in regulating both inflammatory and regulatory functions of T cells during inflammation and infection. It should be noted that the specific DC subset contributing to regulation of T cell responses within the brain and CNS has not been clearly defined, but both DCs and microglia/macrophages are present in the steady-state brain and CNS as early as embryonic day six and remain in adults [74]. Meningeal/choroid plexus DCs (m/chDC) are also present within the CNS and reside in areas of T cell entry into the brain during inflammation [75]. These m/ chDCs are able to present CNS peptides and alloantigens to T cells ex vivo, unlike microglia [76]. Therefore, it is likely that a bona fide DC subset is contributing to the regulation of T cells responses within the brain/CNS.

Conclusions Clearly, the contribution of direct interaction of DCs with T cells in shaping the T cell response to infection goes far beyond the initial priming event in the LN. Direct interactions of tissue-resident DCs with T cells at sites of infection contribute to the activation, effector programming, and memory establishment of these T cells (Fig. 1). While these interactions have been best characterized in the lungs during IAV infections, it remains to be determined whether similar interactions occur in response to other pulmonary challenges. In addition, whether the contribution of direct DC: T cell interactions to T cell function is as broad in the other tissues discussed herein as it is in the lung has not been elucidated. Further, in certain tissues, such as the intestine, skin, and CNS, direct interactions of DCs with T cells have been demonstrated to be tolerizing. Therefore, what determines whether the effects of peripheral DC: T cell interactions on T cells are activating or tolerizing in various tissues during infection remains unclear. This review has focused on DC regulation of T cells in sites where inflammation is tightly regulated because of constant exposure to pathogens (lung, intestines, vagina, skin, and liver) or immune privilege (brain/CNS). It should be noted that peripheral regulation of T cell responses by direct interactions with DCs has also been observed in several other tissues such as the omentum, bone marrow, and thyroid [77–79]. Consequently, it is possible T cells are regulated by direct interaction with DCs in many more

tissues throughout the body, but that these interactions have simply not yet been investigated. Gaining a better understanding of the requirements for direct interactions of DCs with T cells in generating efficient effector and memory T cell responses could aid greatly in future therapeutics and vaccinations designed to boost T cell responses and target them to specific organs to alleviate acute and chronic infections. Acknowledgments We thank Emma E. Hornick for her critical reading of this manuscript. This work was supported by National Institutes of Health awards AI071085 (to K.L.L.), T32 AI007533 (to E.A.H.), and T32 AI007485 (to E.A.H.).

References 1. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811. doi:10.1146/annurev.immunol.18.1.767. 2. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol. 2002;20:621–67. doi:10.1146/annurev. immunol.20.100301.064828. 3. Lambrecht BN, Hammad H. Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu Rev Immunol. 2012;30:243–70. doi:10.1146/annurevimmunol-020711-075021. 4. Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol. 2009;27:591–619. doi:10.1146/annurev. immunol.021908.132706. 5. Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol. 2010;22(3):333– 40. doi:10.1016/j.coi.2010.02.013. 6. Bertram EM, Dawicki W, Watts TH. Role of T cell costimulation in anti-viral immunity. Semin Immunol. 2004;16(3):185–96. doi:10.1016/j.smim.2004.02.006. 7. Welten SP, Melief CJ, Arens R. The distinct role of T cell costimulation in antiviral immunity. Curr Opin Virol. 2013;3(4):475–82. doi:10.1016/j.coviro.2013.06.012. 8. Kaech SM, Ahmed R. Memory CD8? T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol. 2001;2(5):415–22. doi:10.1038/87720. 9. van Stipdonk MJ, Hardenberg G, Bijker MS, Lemmens EE, Droin NM, Green DR, et al. Dynamic programming of CD8? T lymphocyte responses. Nat Immunol. 2003;4(4):361–5. doi:10.1038/ ni912. 10. van Stipdonk MJ, Lemmens EE, Schoenberger SP. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat Immunol. 2001;2(5):423–9. doi:10.1038/87730. 11. Bedoui S, Gebhardt T. Interaction between dendritic cells and T cells during peripheral virus infections: a role for antigen presentation beyond lymphoid organs? Curr Opin Immunol. 2011;23(1):124–30. doi:10.1016/j.coi.2010.11.001. 12. Bennett CL, Chakraverty R. Dendritic cells in tissues: in situ stimulation of immunity and immunopathology. Trends Immunol. 2012;33(1):8–13. doi:10.1016/j.it.2011.09.008. 13. Carragher DM, Rangel-Moreno J, Randall TD. Ectopic lymphoid tissues and local immunity. Semin Immunol. 2008;20(1):26–42. doi:10.1016/j.smim.2007.12.004. 14. Neyt K, Perros F, GeurtsvanKessel CH, Hammad H, Lambrecht BN. Tertiary lymphoid organs in infection and autoimmunity.

123

University of Iowa Immunology 2014

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

Trends Immunol. 2012;33(6):297–305. doi:10.1016/j.it.2012.04. 006. Chiavolini D, Rangel-Moreno J, Berg G, Christian K, OliveiraNascimento L, Weir S, et al. Bronchus-associated lymphoid tissue (BALT) and survival in a vaccine mouse model of tularemia. PLoS One. 2010;5(6):e11156. doi:10.1371/journal.pone.001 1156. Holt PG. Development of bronchus associated lymphoid tissue (BALT) in human lung disease: a normal host defence mechanism awaiting therapeutic exploitation? Thorax. 1993;48(11): 1097–8. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004;10(9):927–34. doi:10.1038/nm1091. Tschernig T, Pabst R. Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases. Pathobiology. 2000;68(1):1–8. Moyron-Quiroz J, Rangel-Moreno J, Carragher DM, Randall TD. The function of local lymphoid tissues in pulmonary immune responses. Adv Exp Med Biol. 2007;590:55–68. doi:10.1007/ 978-0-387-34814-8_4. GeurtsvanKessel CH, Willart MA, Bergen IM, van Rijt LS, Muskens F, Elewaut D, et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med. 2009;206(11):2339–49. doi:10.1084/jem.20090410. Belz GT, Smith CM, Kleinert L, Reading P, Brooks A, Shortman K, et al. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc Natl Acad Sci USA. 2004;101(23):8670–5. doi:10.1073/pnas.0402644101. Brincks EL, Katewa A, Kucaba TA, Griffith TS, Legge KL. CD8 T cells utilize TRAIL to control influenza virus infection. J Immunol. 2008;181(7):4918–25. GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, et al. Clearance of influenza virus from the lung depends on migratory langerin? CD11b- but not plasmacytoid dendritic cells. J Exp Med. 2008;205(7):1621–34. doi:10.1084/ jem.20071365. Kim TS, Braciale TJ. Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8? T cell responses. PLoS One. 2009;4(1):e4204. doi:10. 1371/journal.pone.0004204. Legge KL, Braciale TJ. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. Immunity. 2003;18(2):265–77. McGill J, Legge KL. Cutting edge: contribution of lung-resident T cell proliferation to the overall magnitude of the antigen-specific CD8 T cell response in the lungs following murine influenza virus infection. J Immunol. 2009;183(7):4177–81. doi:10.4049/ jimmunol.0901109. McGill J, Van Rooijen N, Legge KL. Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J Exp Med. 2008;205(7):1635–46. doi:10.1084/ jem.20080314. McGill J, Van Rooijen N, Legge KL. IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection. J Exp Med. 2010;207(3):521–34. doi:10.1084/jem.20091711. Halle S, Dujardin HC, Bakocevic N, Fleige H, Danzer H, Willenzon S, et al. Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. J Exp Med. 2009;206(12):2593–601. doi:10.1084/ jem.20091472.

123

30. Marshall DR, Turner SJ, Belz GT, Wingo S, Andreansky S, Sangster MY, et al. Measuring the diaspora for virus-specific CD8? T cells. Proc Natl Acad Sci USA. 2001;98(11):6313–8. doi:10.1073/pnas.101132698. 31. Kohlmeier JE, Miller SC, Woodland DL. Cutting edge: antigen is not required for the activation and maintenance of virus-specific memory CD8? T cells in the lung airways. J Immunol. 2007;178(8):4721–5. 32. Hogan RJ, Usherwood EJ, Zhong W, Roberts AA, Dutton RW, Harmsen AG, et al. Activated antigen-specific CD8? T cells persist in the lungs following recovery from respiratory virus infections. J Immunol. 2001;166(3):1813–22. 33. Roberts AD, Woodland DL. Cutting edge: effector memory CD8? T cells play a prominent role in recall responses to secondary viral infection in the lung. J Immunol. 2004;172(11): 6533–7. 34. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708–12. doi:10. 1038/44385. 35. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol. 2003;4(3):225–34. doi:10.1038/ni889. 36. Topham DJ, Castrucci MR, Wingo FS, Belz GT, Doherty PC. The role of antigen in the localization of naive, acutely activated, and memory CD8(?) T cells to the lung during influenza pneumonia. J Immunol. 2001;167(12):6983–90. 37. Yewdell JW, Bennink JR. Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu Rev Immunol. 1999;17:51–88. doi:10.1146/annurev. immunol.17.1.51. 38. Piet B, de Bree GJ, Smids-Dierdorp BS, van der Loos CM, Remmerswaal EB, von der Thusen JH, et al. CD8(?) T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. J Clin Investig. 2011;121(6):2254–63. doi:10.1172/JCI44675. 39. Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, Kusser K, Tighe MP, Klonowski KD, et al. Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity. 2006;25(4):643–54. doi:10.1016/j.immuni. 2006.08.022. 40. Kim TS, Hufford MM, Sun J, Fu YX, Braciale TJ. Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection. J Exp Med. 2010;207(6):1161–72. doi:10.1084/jem.20092017. 41. Inman CF, Singha S, Lewis M, Bradley B, Stokes C, Bailey M. Dendritic cells interact with CD4 T cells in intestinal mucosa. J Leukoc Biol. 2010;88(3):571–8. doi:10.1189/jlb.0310161. 42. Johansson-Lindbom B, Svensson M, Wurbel MA, Malissen B, Marquez G, Agace W. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J Exp Med. 2003;198(6): 963–9. doi:10.1084/jem.20031244. 43. Mora JR, Cheng G, Picarella D, Briskin M, Buchanan N, von Andrian UH. Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J Exp Med. 2005;201(2):303–16. doi:10.1084/jem. 20041645. 44. Klonowski KD, Marzo AL, Williams KJ, Lee SJ, Pham QM, Lefrancois L. CD8 T cell recall responses are regulated by the tissue tropism of the memory cell and pathogen. J Immunol. 2006;177(10):6738–46. 45. Iijima N, Mattei LM, Iwasaki A. Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue.

University of Iowa Immunology 2014

46.

47.

48. 49. 50. 51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

Proc Natl Acad Sci USA. 2011;108(1):284–9. doi:10.1073/pnas. 1005201108. Lehner T, Panagiotidi C, Bergmeier LA, Tao L, Brookes R, Gearing A, et al. Genital-associated lymphoid tissue in female non-human primates. Adv Exp Med Biol. 1995;371A:357–65. Zhu J, Koelle DM, Cao J, Vazquez J, Huang ML, Hladik F, et al. Virus-specific CD8? T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med. 2007;204(3):595–603. doi:10.1084/jem.20061792. Streilein JW. Lymphocyte traffic, T-cell malignancies and the skin. J Invest Dermatol. 1978;71(3):167–71. Streilein JW. Skin-associated lymphoid tissues (SALT): origins and functions. J Invest Dermatol. 1983;80(Suppl):12s–6s. Streilein JW. Circuits and signals of the skin-associated lymphoid tissues (SALT). J Invest Dermatol. 1985;85(1 Suppl):10s–3s. Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, Hashimoto D, et al. The origin and development of nonlymphoid tissue CD103? DCs. J Exp Med. 2009;206(13):3115–30. doi:10.1084/ jem.20091756. Heath WR, Carbone FR. Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nat Immunol. 2009;10(12):1237–44. doi:10.1038/ni.1822. Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol. 2012;13(9):888–99. doi:10.1038/ni.2370. Toews GB, Bergstresser PR, Streilein JW. Langerhans cells: sentinels of skin associated lymphoid tissue. J Invest Dermatol. 1980;75(1):78–82. Bedoui S, Whitney PG, Waithman J, Eidsmo L, Wakim L, Caminschi I, et al. Cross-presentation of viral and self antigens by skin-derived CD103? dendritic cells. Nat Immunol. 2009;10(5):488–95. doi:10.1038/ni.1724. McLachlan JB, Catron DM, Moon JJ, Jenkins MK. Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin. Immunity. 2009;30(2):277–88. doi:10.1016/j.immuni.2008.11.013. Seneschal J, Clark RA, Gehad A, Baecher-Allan CM, Kupper TS. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity. 2012;36(5):873–84. doi:10.1016/j.immuni.2012.03.018. Bennett CL, Fallah-Arani F, Conlan T, Trouillet C, Goold H, Chorro L, et al. Langerhans cells regulate cutaneous injury by licensing CD8 effector cells recruited to the skin. Blood. 2011;117(26):7063–9. doi:10.1182/blood-2011-01-329185. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, et al. Different patterns of peripheral migration by memory CD4? and CD8? T cells. Nature. 2011;477(7363):216– 9. doi:10.1038/nature10339. Heath WR, Carbone FR. The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol. 2013;14(10):978–85. doi:10.1038/ni.2680. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN, et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci USA. 2012;109(18):7037–42. doi:10.1073/pnas.1202288109. Hino K, Okuda M, Konishi T, Yamashita A, Kayano K, Kubota M, et al. Analysis of lymphoid follicles in liver of patients with chronic hepatitis C. Liver. 1992;12(6):387–91. Shomer NH, Fox JG, Juedes AE, Ruddle NH. Helicobacterinduced chronic active lymphoid aggregates have characteristics of tertiary lymphoid tissue. Infect Immun. 2003;71(6):3572–7. Yoneyama H, Matsuno K, Zhang Y, Murai M, Itakura M, Ishikawa S, et al. Regulation by chemokines of circulating

65. 66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease. J Exp Med. 2001;193(1):35–49. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147–63. doi:10.1146/annurev.immunol.021908.132629. Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z, et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(?) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol. 2013;14(6):574–83. doi:10.1038/ni.2573. Lauer GM. Hepatitis C virus-specific CD8? T cells restricted by donor HLA alleles following liver transplantation. Liver Transpl. 2005;11(7):848–50. doi:10.1002/lt.20423. Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest. 2004;114(5):701–12. doi:10.1172/JCI21593. Klein I, Crispe IN. Complete differentiation of CD8? T cells activated locally within the transplanted liver. J Exp Med. 2006;203(2):437–47. doi:10.1084/jem.20051775. Klonowski KD, Williams KJ, Marzo AL, Blair DA, Lingenheld EG, Lefrancois L. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity. 2004;20(5):551–62. Wakim LM, Woodward-Davis A, Bevan MJ. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc Natl Acad Sci USA. 2010;107(42):17872–9. doi:10.1073/pnas.1010201107. Wakim LM, Waithman J, van Rooijen N, Heath WR, Carbone FR. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science. 2008;319(5860):198–202. doi:10. 1126/science.1151869. Bartholomaus I, Kawakami N, Odoardi F, Schlager C, Miljkovic D, Ellwart JW, et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009;462(7269):94–8. doi:10.1038/nature08478. Bulloch K, Miller MM, Gal-Toth J, Milner TA, GottfriedBlackmore A, Waters EM, et al. CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J Comp Neurol. 2008;508(5):687–710. doi:10.1002/cne.21668. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, et al. C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol. 2009;10(5):514–23. doi:10. 1038/ni.1716. Anandasabapathy N, Victora GD, Meredith M, Feder R, Dong B, Kluger C, et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steadystate mouse brain. J Exp Med. 2011;208(8):1695–705. doi:10. 1084/jem.20102657. Milo I, Sapoznikov A, Kalchenko V, Tal O, Krauthgamer R, van Rooijen N, et al. Dynamic imaging reveals promiscuous cross presentation of blood-borne antigens to naive CD8? T cells in the bone marrow. Blood. 2013;122(2):193–208. doi:10.1182/ blood-2012-01-401265. Muniz LR, Pacer ME, Lira SA, Furtado GC. A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. J Immunol. 2011;187(2):828–34. doi:10.4049/jimmunol.1004233. Rangel-Moreno J, Moyron-Quiroz JE, Carragher DM, Kusser K, Hartson L, Moquin A, et al. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity. 2009;30(5):731–43. doi:10.1016/j.immuni.2009.03.014.

123

Peripheral regulation of T cells by dendritic cells during infection.

It is well accepted that T cell responses are integral in providing protection during pathogenic infections. In numerous tissues, T cell responses are...
308KB Sizes 0 Downloads 5 Views