Cellular & Molecular Immunology (2014) 11, 323–325 ß 2014 CSI and USTC. All rights reserved 1672-7681/14 $32.00 www.nature.com/cmi
RESEARCH HIGHLIGHT
Loss of TCR responsiveness during thymic education imprints the ‘innate’ signature on cd T cells Sundararajan Jayaraman Cellular & Molecular Immunology (2014) 11, 323–325; doi:10.1038/cmi.2014.10; published online 7 April 2014
T
cells expressing cd determinants are considered innate-like and deviate from the classical ab T cells in many aspects, including the rapid production of lymphokines following the recognition of ‘naked’ antigens by the invariant T-cell receptor and failure to differentiate in the periphery. The details of thymic maturation in these atypical T cells have remained unclear. Recently, Wencker et al. demonstrated that during thymic education, cd T cells acquire innate-like characteristics following the attrition of T-cell receptor (TCR)mediated signaling.1 This previously unrecognized attribute could serve as a criterion for the subdivision of mature cd T cells into subtypes. The adaptive immune system, endowed with the unique ability to distinguish non-self from self and to retain memory for recall responses to a myriad of antigens, is a privilege of vertebrates, ranging from primitive jawless fish to mammals. The innate immune system is remarkably different from the adaptive immune system in these aspects and is highly conserved among the members of the plant and animal kingdoms. The ancient innate immune system has evolved various defense mechanisms under selective pressure in the form of bacterial and viral infections.2 In Department of Surgery, University of Illinois College of Medicine, Peoria, IL, USA Correspondence: Dr S Jayaraman, Department of Surgery, University of Illinois College of Medicine, Peoria, IL, USA. E-mail: [email protected] Received: 22 January 2014; Revised: 23 January 2014; Accepted: 23 January 2014
higher-order vertebrates, the innate immune system is represented by monocytes and their derivatives, such as dendritic cells. These cells are an integral part of the organized central and peripheral lymphoid tissues; they function as antigen presenting cells to the ab T cells of the adaptive immune system. The complexity of ab T cells for the most part has been revealed in the last 60 years. Recent years have witnessed the existence of a parallel universe of the adaptive immune system, uncovering at least three major types of innate lymphoid cells (ILCs) with distinguishable expression of transcription factors, similar to the CD41 ab T cells.3–5 Whereas the natural killer-like ILC1 cells express T-bet and produce IFN-c, the Th2-like ILC2 cells are GATA-31 and produce IL-4. The ILC3 cells are phenotypically heterogeneous and express various transcription factors. The lymphocytic inducer T cells colonize the gut-associated lymphoid patches early on during ontogeny and express T-bet. The NKp461 ILC3 cell type expresses T-bet, IFN-c, and as IL-22, cytokines that are considered characteristic of the Th17 subset. The Th17-like CCR61 ILC3 cell type expresses RORct, resulting in the transcription of IL-17A/F. In the face of this new knowledge about the ILCs, it is intriguing to consider whether a similar division of labor exists among the cd T cells that assume a special niche in the immune system. The gut stockpiles most (80%) of the cd T cells in the body that constitute 5%– 10% of the intestinal T cells.6 Although
cd T cells have long been thought to straddle the innate and adaptive immune systems, definite proof for this notion has remained elusive. Unlike the ab T cells that recognize peptide antigens in the context of self-major histocompatibility complex-encoded determinants, cd T cells have been proposed to recognize peptidic and non-peptidic determinants associated with bacteria and viruses in a non-major histocompatibility complex-restricted manner, as do B cells.7 It is intriguing how cd T cells that lack clonotypic receptors but putatively possess polyspecific receptors8 are involved in self-tolerance induction as they have a purported role in autoimmune diseases.9,10 The ab T cells undergo elaborate differentiation in the periphery, which endows these cells with the capacity to respond specifically to antigen receptor-mediated stimulation and avoid the spurious consequences of bystander activation by unspecific cytokines. In contrast, cd T cells are abundant in the neonate and afford protection against infections and also contribute to immunopathologies,8,11 and yet, the role of TCR signaling in shaping these innate cells remained obscure. Wencker et al.1 addressed this important question in cd cells that lack the costimulatory receptor CD27 (CD272 cd cells) and rapidly produce IL-17A, typical of innate-like cells. These cells constitutively express TCRhiIL-7RhiIL1RhiCD62LloCD44hi, which is indicative of developmental pre-programming, and are therefore ideal for this investigation. They found that the frequency of
Research Highlight
324
CD272 cd cells was reduced in SKG mice, which carry a mutation that profoundly reduces the function of the TCR proximal kinase Zap70,12 indicating the requirement for T-cell activation during ontogeny. Production of IL-17 was also reduced in response to pharmacological activation in these cells.1 In addition, the frequency of CCR6 expressing CD272 cd cells was also decreased in the spleen and lymph nodes, and importantly, in the dermis of the SKG mice. In stark contrast, CD271 cd cells that produce IFN-c were barely affected, indicating the dependency on Zap70 for the development of cd CD272 cells, a previously unknown criterion for the subdivision of innate cd cells. In support of the requirement of TCR activation during thymic selection in CD272 cd cells, two early events during T-cell activation, intracellular Ca21 mobilization and the phosphorylation of Erk kinase were reduced in Zap70 mutant mice. Using Nur77-GFP reporter mice, it was further shown that cd CD272 cells have an impaired ability to respond to TCR crosslinking. Consistent with these observations, peripheral cd CD272 cells from wild-type mice also showed diminished calcium influx in response to treatment with an agonist antibody to the TCR. Substitution with IL-7 did not improve the calcium response elicited by TCR signaling. In contrast with CD271 cd cells, most cd CD272 cells produced IL-17 when stimulated with IL-1b and IL-23, indicating that these
cells can respond to innate stimuli, despite compromised TCR signaling. These findings were also reproduced in a distinct subset of innate-like T cells, dendritic epidermal T cells that express Vc51Vd11 and produce IFN-c and IL13 but not IL-17A. Thus, dendritic epidermal T cells are also dependent on discrete TCR signaling for development via the recognition of Skint1, which suppressed Rorc and Il17a, and upregulated CD45RB, Tbx21 and Ifng. Wencker et al.1 also observed that, similar to the cd CD272 cells, dendritic epidermal T cells also acquire TCR hyporesponsiveness during maturation as indicated by attenuated calcium influx and reduced phosphorylation of Erk and Src upon crosslinking of the TCR.1 Most innate-like T cells require TCR signaling for development, whereas mature cells attenuate TCR-mediated responsiveness, which led to the identification of an additional thymocyte subset that expresses CD27145RBhi and produces IFN-c in response to stimulation with IL-12 and IL-18 with or without IL-15.1 This subset was depleted in SKG mice, indicating the dependence on TCR signaling for its development leading to an attenuated calcium response and the phosphorylation of Erk similar to other innate-like T cells discussed above (Figure 1). Importantly, the signaling components associated with hyporesponsive/anergic ab cells, such as Egr2/3, are not expressed in these hyporesponsive innate-like cells. In
Thymus Precursor gd
Precursor gd Loss of TCR signaling response Mature gd
Periphery: Circulation IL-1b, IL-23 Skin IL-12, IL-18, IL-15 Lung Gut
Mature gd
gd CD27–
IL-17A
gd CD27+, CD45RBhi Vg5+Vd1+
DETC
IFN-g IFN-g, IL-13
Intestinal Immunity Autoimmunity Antigen Presentation
Figure 1 A model depicting the role of TCR signaling during the maturation of cd innate-like cells that produce various lymphokines. DETC, dendritic epidermal T cell; TCR, T-cell receptor. Cellular & Molecular Immunology
contrast, conventional ab T cells and invariant natural killer T cells remain unaltered in SKG mice, indicating a lack of TCR signaling for development; this observation is supported by the conventional TCR responsiveness observed in the Nur-77 reporter mice. However, the ab1 and cd1 T cells residing in the intestine are developmentally Syk-dependent and demonstrate TCR hyporesponsiveness.1 Wencker et al.1 proposed that innatelike T cells straddle the innate and adaptive immune system by altering the responsiveness of the TCR during development. Whereas the engagement of the TCR signaling for development in cd cells is similar to adaptive T cells, the attenuation of TCR signaling at the mature stage and the responsiveness to nonspecific signals simulates the innate cells. These hyporesponsive innate T cells do not resemble the anergic or hyporesponsive ab T cells. Elucidation of the underlying molecular mechanisms will uncover yet other similarities or variances between these T cells belonging to apparently different entities: the adaptive and innate immune systems. cd T cells were discovered based on their expression of cell surface-associated determinants associated with CD3 and not necessarily because of their functional properties.13 Unlike their ab counterparts, cd cells have received relatively little attention over the years; only recently has the importance of these cells in the immune system been highlighted.14 Recent work by the Hayday Lab1 provides an impetus to critically analyze many unexplained attributes of cd cells that assume an innate role during thymic education. These include the nature of thymic selection, expression of CD4 and CD8 and costimulatory determinants, the mode of antigen recognition in the periphery, the interconversion (plasticity) of various cd subsets, and importantly, the downstream signaling pathway coupled to the TCR. Although cd T cells in general have been associated with immunity against certain pathogens, it is unclear how they perform these important functions in a specific manner. Answers to these questions will bolster the role of this unconventional T-cell subset in the integrity of the immune system
Research Highlight
325
without compromising defenses against dangers from the external milieu, in the form of infections, as well as within the body, in the form of transformed cells.
1 Wencker M, Turchinovich G, Di Marco Barros R, Deban L, Jandke A, Cope A et al. Innate-like T cells straddle innate and adaptive immunity by altering antigenreceptor responsiveness. Nat Immunol 2014; 15: 80–87. 2 Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91: 295–298. 3 Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol 2013; 13: 145–149.
4 Bernink J, Mjo¨ sberg J, Spits H. Th1- and Th2-like subsets of innate lymphoid cells. Immunol Rev 2013; 252: 133– 138. 5 Jayaraman S. T-bet in the spot light: roles in distinct T-cell fate determination. Cell Mol Immunol 2013; 10: 289–291. 6 Bucy RP, Chen CL, Cooper MD. Tissue localization and CD8 accessory molecule expression of T gamma delta cells in humans. J Immunol 1989; 142: 3045– 3049. 7 Chien YH, Jores R, Crowley MP. Recognition by gamma/delta T cells. Annu Rev Immunol 1996; 14: 511–532. 8 Born WK, Kemal Aydintug M, O’Brien RL. Diversity of cd T-cell antigens. Cell Mol Immunol 2013; 10: 13–20. 9 Su D, Shen M, Li X, Sun L. Roles of cd T cells in the pathogenesis of autoimmune diseases. Clin Dev Immunol 2013; 2013: 985753.
10 Markle JG, Mortin-Toth S, Wong AS, Geng L, Hayday A, Danska JS. cd T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model. J Immunol 2013; 190: 5392–5401. 11 Ferreira LM. Gammadelta T cells: innately adaptive immune cells? Int Rev Immunol 2013; 32: 223–248. 12 Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 2003; 426: 454– 460. 13 Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA, Owen FL et al. Identification of a putative second T-cell receptor. Nature 1986; 322: 145–149. 14 Vantourout P, Hayday A. Six-of-the-best: unique contributions of cd T cells to immunology. Nat Rev Immunol 2013; 13: 88–100.
Cellular & Molecular Immunology
RESEARCH HIGHLIGHT
Loss of TCR responsiveness during thymic education imprints the ‘innate’ signature on cd T cells Sundararajan Jayaraman Cellular & Molecular Immunology (2014) 11, 323–325; doi:10.1038/cmi.2014.10; published online 7 April 2014
T
cells expressing cd determinants are considered innate-like and deviate from the classical ab T cells in many aspects, including the rapid production of lymphokines following the recognition of ‘naked’ antigens by the invariant T-cell receptor and failure to differentiate in the periphery. The details of thymic maturation in these atypical T cells have remained unclear. Recently, Wencker et al. demonstrated that during thymic education, cd T cells acquire innate-like characteristics following the attrition of T-cell receptor (TCR)mediated signaling.1 This previously unrecognized attribute could serve as a criterion for the subdivision of mature cd T cells into subtypes. The adaptive immune system, endowed with the unique ability to distinguish non-self from self and to retain memory for recall responses to a myriad of antigens, is a privilege of vertebrates, ranging from primitive jawless fish to mammals. The innate immune system is remarkably different from the adaptive immune system in these aspects and is highly conserved among the members of the plant and animal kingdoms. The ancient innate immune system has evolved various defense mechanisms under selective pressure in the form of bacterial and viral infections.2 In Department of Surgery, University of Illinois College of Medicine, Peoria, IL, USA Correspondence: Dr S Jayaraman, Department of Surgery, University of Illinois College of Medicine, Peoria, IL, USA. E-mail: [email protected] Received: 22 January 2014; Revised: 23 January 2014; Accepted: 23 January 2014
higher-order vertebrates, the innate immune system is represented by monocytes and their derivatives, such as dendritic cells. These cells are an integral part of the organized central and peripheral lymphoid tissues; they function as antigen presenting cells to the ab T cells of the adaptive immune system. The complexity of ab T cells for the most part has been revealed in the last 60 years. Recent years have witnessed the existence of a parallel universe of the adaptive immune system, uncovering at least three major types of innate lymphoid cells (ILCs) with distinguishable expression of transcription factors, similar to the CD41 ab T cells.3–5 Whereas the natural killer-like ILC1 cells express T-bet and produce IFN-c, the Th2-like ILC2 cells are GATA-31 and produce IL-4. The ILC3 cells are phenotypically heterogeneous and express various transcription factors. The lymphocytic inducer T cells colonize the gut-associated lymphoid patches early on during ontogeny and express T-bet. The NKp461 ILC3 cell type expresses T-bet, IFN-c, and as IL-22, cytokines that are considered characteristic of the Th17 subset. The Th17-like CCR61 ILC3 cell type expresses RORct, resulting in the transcription of IL-17A/F. In the face of this new knowledge about the ILCs, it is intriguing to consider whether a similar division of labor exists among the cd T cells that assume a special niche in the immune system. The gut stockpiles most (80%) of the cd T cells in the body that constitute 5%– 10% of the intestinal T cells.6 Although
cd T cells have long been thought to straddle the innate and adaptive immune systems, definite proof for this notion has remained elusive. Unlike the ab T cells that recognize peptide antigens in the context of self-major histocompatibility complex-encoded determinants, cd T cells have been proposed to recognize peptidic and non-peptidic determinants associated with bacteria and viruses in a non-major histocompatibility complex-restricted manner, as do B cells.7 It is intriguing how cd T cells that lack clonotypic receptors but putatively possess polyspecific receptors8 are involved in self-tolerance induction as they have a purported role in autoimmune diseases.9,10 The ab T cells undergo elaborate differentiation in the periphery, which endows these cells with the capacity to respond specifically to antigen receptor-mediated stimulation and avoid the spurious consequences of bystander activation by unspecific cytokines. In contrast, cd T cells are abundant in the neonate and afford protection against infections and also contribute to immunopathologies,8,11 and yet, the role of TCR signaling in shaping these innate cells remained obscure. Wencker et al.1 addressed this important question in cd cells that lack the costimulatory receptor CD27 (CD272 cd cells) and rapidly produce IL-17A, typical of innate-like cells. These cells constitutively express TCRhiIL-7RhiIL1RhiCD62LloCD44hi, which is indicative of developmental pre-programming, and are therefore ideal for this investigation. They found that the frequency of
Research Highlight
324
CD272 cd cells was reduced in SKG mice, which carry a mutation that profoundly reduces the function of the TCR proximal kinase Zap70,12 indicating the requirement for T-cell activation during ontogeny. Production of IL-17 was also reduced in response to pharmacological activation in these cells.1 In addition, the frequency of CCR6 expressing CD272 cd cells was also decreased in the spleen and lymph nodes, and importantly, in the dermis of the SKG mice. In stark contrast, CD271 cd cells that produce IFN-c were barely affected, indicating the dependency on Zap70 for the development of cd CD272 cells, a previously unknown criterion for the subdivision of innate cd cells. In support of the requirement of TCR activation during thymic selection in CD272 cd cells, two early events during T-cell activation, intracellular Ca21 mobilization and the phosphorylation of Erk kinase were reduced in Zap70 mutant mice. Using Nur77-GFP reporter mice, it was further shown that cd CD272 cells have an impaired ability to respond to TCR crosslinking. Consistent with these observations, peripheral cd CD272 cells from wild-type mice also showed diminished calcium influx in response to treatment with an agonist antibody to the TCR. Substitution with IL-7 did not improve the calcium response elicited by TCR signaling. In contrast with CD271 cd cells, most cd CD272 cells produced IL-17 when stimulated with IL-1b and IL-23, indicating that these
cells can respond to innate stimuli, despite compromised TCR signaling. These findings were also reproduced in a distinct subset of innate-like T cells, dendritic epidermal T cells that express Vc51Vd11 and produce IFN-c and IL13 but not IL-17A. Thus, dendritic epidermal T cells are also dependent on discrete TCR signaling for development via the recognition of Skint1, which suppressed Rorc and Il17a, and upregulated CD45RB, Tbx21 and Ifng. Wencker et al.1 also observed that, similar to the cd CD272 cells, dendritic epidermal T cells also acquire TCR hyporesponsiveness during maturation as indicated by attenuated calcium influx and reduced phosphorylation of Erk and Src upon crosslinking of the TCR.1 Most innate-like T cells require TCR signaling for development, whereas mature cells attenuate TCR-mediated responsiveness, which led to the identification of an additional thymocyte subset that expresses CD27145RBhi and produces IFN-c in response to stimulation with IL-12 and IL-18 with or without IL-15.1 This subset was depleted in SKG mice, indicating the dependence on TCR signaling for its development leading to an attenuated calcium response and the phosphorylation of Erk similar to other innate-like T cells discussed above (Figure 1). Importantly, the signaling components associated with hyporesponsive/anergic ab cells, such as Egr2/3, are not expressed in these hyporesponsive innate-like cells. In
Thymus Precursor gd
Precursor gd Loss of TCR signaling response Mature gd
Periphery: Circulation IL-1b, IL-23 Skin IL-12, IL-18, IL-15 Lung Gut
Mature gd
gd CD27–
IL-17A
gd CD27+, CD45RBhi Vg5+Vd1+
DETC
IFN-g IFN-g, IL-13
Intestinal Immunity Autoimmunity Antigen Presentation
Figure 1 A model depicting the role of TCR signaling during the maturation of cd innate-like cells that produce various lymphokines. DETC, dendritic epidermal T cell; TCR, T-cell receptor. Cellular & Molecular Immunology
contrast, conventional ab T cells and invariant natural killer T cells remain unaltered in SKG mice, indicating a lack of TCR signaling for development; this observation is supported by the conventional TCR responsiveness observed in the Nur-77 reporter mice. However, the ab1 and cd1 T cells residing in the intestine are developmentally Syk-dependent and demonstrate TCR hyporesponsiveness.1 Wencker et al.1 proposed that innatelike T cells straddle the innate and adaptive immune system by altering the responsiveness of the TCR during development. Whereas the engagement of the TCR signaling for development in cd cells is similar to adaptive T cells, the attenuation of TCR signaling at the mature stage and the responsiveness to nonspecific signals simulates the innate cells. These hyporesponsive innate T cells do not resemble the anergic or hyporesponsive ab T cells. Elucidation of the underlying molecular mechanisms will uncover yet other similarities or variances between these T cells belonging to apparently different entities: the adaptive and innate immune systems. cd T cells were discovered based on their expression of cell surface-associated determinants associated with CD3 and not necessarily because of their functional properties.13 Unlike their ab counterparts, cd cells have received relatively little attention over the years; only recently has the importance of these cells in the immune system been highlighted.14 Recent work by the Hayday Lab1 provides an impetus to critically analyze many unexplained attributes of cd cells that assume an innate role during thymic education. These include the nature of thymic selection, expression of CD4 and CD8 and costimulatory determinants, the mode of antigen recognition in the periphery, the interconversion (plasticity) of various cd subsets, and importantly, the downstream signaling pathway coupled to the TCR. Although cd T cells in general have been associated with immunity against certain pathogens, it is unclear how they perform these important functions in a specific manner. Answers to these questions will bolster the role of this unconventional T-cell subset in the integrity of the immune system
Research Highlight
325
without compromising defenses against dangers from the external milieu, in the form of infections, as well as within the body, in the form of transformed cells.
1 Wencker M, Turchinovich G, Di Marco Barros R, Deban L, Jandke A, Cope A et al. Innate-like T cells straddle innate and adaptive immunity by altering antigenreceptor responsiveness. Nat Immunol 2014; 15: 80–87. 2 Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91: 295–298. 3 Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol 2013; 13: 145–149.
4 Bernink J, Mjo¨ sberg J, Spits H. Th1- and Th2-like subsets of innate lymphoid cells. Immunol Rev 2013; 252: 133– 138. 5 Jayaraman S. T-bet in the spot light: roles in distinct T-cell fate determination. Cell Mol Immunol 2013; 10: 289–291. 6 Bucy RP, Chen CL, Cooper MD. Tissue localization and CD8 accessory molecule expression of T gamma delta cells in humans. J Immunol 1989; 142: 3045– 3049. 7 Chien YH, Jores R, Crowley MP. Recognition by gamma/delta T cells. Annu Rev Immunol 1996; 14: 511–532. 8 Born WK, Kemal Aydintug M, O’Brien RL. Diversity of cd T-cell antigens. Cell Mol Immunol 2013; 10: 13–20. 9 Su D, Shen M, Li X, Sun L. Roles of cd T cells in the pathogenesis of autoimmune diseases. Clin Dev Immunol 2013; 2013: 985753.
10 Markle JG, Mortin-Toth S, Wong AS, Geng L, Hayday A, Danska JS. cd T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model. J Immunol 2013; 190: 5392–5401. 11 Ferreira LM. Gammadelta T cells: innately adaptive immune cells? Int Rev Immunol 2013; 32: 223–248. 12 Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 2003; 426: 454– 460. 13 Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA, Owen FL et al. Identification of a putative second T-cell receptor. Nature 1986; 322: 145–149. 14 Vantourout P, Hayday A. Six-of-the-best: unique contributions of cd T cells to immunology. Nat Rev Immunol 2013; 13: 88–100.
Cellular & Molecular Immunology
