How the TCR balances sensitivity and specificity for the recognition of self and pathogens

Nature Immunology

Volumn 13, Issue 2, 2012, Pages 121-128

  Morris, Gerald P ^a   Allen, Paul M ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 7; LIGAND; MAJOR HISTOCOMPATIBILITY ANTIGEN; T LYMPHOCYTE RECEPTOR; T LYMPHOCYTE RECEPTOR ALPHA CHAIN; T LYMPHOCYTE RECEPTOR BETA CHAIN;

ALLOIMMUNITY; ANTIGEN RECOGNITION; BINDING AFFINITY; CD8+ T LYMPHOCYTE; CELL COMMUNICATION; CELL MEMBRANE; COMPLEMENTARITY DETERMINING REGION; CONFORMATIONAL TRANSITION; HOMEOSTASIS; IMMUNE RESPONSE; IMMUNITY; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; REVIEW; SENSITIVITY AND SPECIFICITY; SIGNAL TRANSDUCTION; THYMOCYTE;

ANIMALS; AUTOANTIGENS; HOST-PATHOGEN INTERACTIONS; HUMANS; MAJOR HISTOCOMPATIBILITY COMPLEX; MALE; MICE; RECEPTORS, ANTIGEN, T-CELL; SELF TOLERANCE; SIGNAL TRANSDUCTION; T-LYMPHOCYTES; THYMOCYTES;

EID: 84855957129     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.2190     Document Type: Review

References (118)

1. Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591-619 (2009).
2. Fraser, I. D. & Germain, R. N. Navigating the network: signaling cross-talk in hematopoietic cells. Nat. Immunol. 10, 327-331 (2009).
3. Hogquist, K. A. et al. Identifi cation of a naturally occurring ligand for thymic positive selection. Immunity 6, 389-399 (1997). (Pubitemid 27208194)
4. Hu, Q. et al. Specifi c recognition of thymic self-peptides induces the positive selection of cytotoxic T lymphocytes. Immunity 7, 221-231 (1997). (Pubitemid 27392014)
5. Lo, W. L. et al. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4 + T cells. Nat. Immunol. 10, 1155-1161 (2009).
6. Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat. Immunol. 10, 1162-1169 (2009).
7. Evavold, B. D. & Allen, P. M. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science 252, 1308-1310 (1991). (Pubitemid 21917045)
8. Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17-27 (1994). (Pubitemid 24035278)
9. Rudolph, M. G., Stanfi eld, R. L. & Wilson, I. A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419-466 (2006).
10. Zerrahn, J., Held, W. & Raulet, D. H. The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627-636 (1997). (Pubitemid 27152405)
11. Feng, D., Bond, C. J., Ely, L. K., Maynard, J. & Garcia, K. C. Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction ' codon '. Nat. Immunol. 8, 975-983 (2007). (Pubitemid 47300012)
12. Dai, S. et al. Crossreactive T cells spotlight the germline rules forαβT cellreceptor interactions with MHC molecules. Immunity 28, 324-334 (2008).
13. Scott-Browne, J. P., White, J., Kappler, J. W., Gapin, L. & Marrack, P. Germlineencoded amino acids in the αβT-cell receptor control thymic selection. Nature 458, 1043-1046 (2009).
14. Morris, G. P., Ni, P. P. & Allen, P. M. Alloreactivity is limited by the endogenous peptide repertoire. Proc. Natl. Acad. Sci. USA 108, 3695-3700 (2011).
15. Yin, L. et al. A single T cell receptor bound to major histocompatibility complex class I and class II glycoproteins reveals switchable TCR conformers. Immunity 35, 23-33 (2011).
16. Wu, L. C., Tuot, D. S., Lyons, D. S., Garcia, K. C. & Davis, M. M. Two-step binding mechanism for T-cell receptor recognition of peptide MHC. Nature 418, 552-556 (2002). (Pubitemid 34851403)
17. Felix, N. J. et al. Alloreactive T cells respond specifi cally to multiple distinct peptide-MHC complexes. Nat. Immunol. 8, 388-397 (2007). (Pubitemid 46745414)
18. Garcia, K. C., Adams, J. J., Feng, D. & Ely, L. K. The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat. Immunol. 10, 143-147 (2009).
19. Huseby, E. S. et al. How the T cell repertoire becomes peptide and MHC specifi c. Cell 122, 247-260 (2005). (Pubitemid 41032988)
20. Matsui, K. et al. Low affi nity interaction of peptide-MHC complexes with T cell receptors. Science 254, 1788-1791 (1991). (Pubitemid 21917527)
21. Huang, J. et al. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464, 932-936 (2010).
22. Huppa, J. B. et al. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affi nity. Nature 463, 963-967 (2010).
23. Sloan-Lancaster, J., Evavold, B. D. & Allen, P. M. Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature 363, 156-159 (1993). (Pubitemid 23147012)
24. Sloan-Lancaster, J., Shaw, A. S., Rothbard, J. B. & Allen, P. M. Partial T cell signaling: altered phospho-and lack of zap70 recruitment in APL-induced T cell anergy. Cell 79, 913-922 (1994). (Pubitemid 24371981)
25. Hogquist, K. A., Jameson, S. C. & Bevan, M. J. Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8 + T cells. Immunity 3, 79-86 (1995).
26. Sebzda, E. et al. Mature T cell reactivity altered by peptide agonist that induces positive selection. J. Exp. Med. 183, 1093-1104 (1996). (Pubitemid 26114803)
27. Kersh, E. N., Shaw, A. S. & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor phosphorylation. Science 281, 572-575 (1998). (Pubitemid 28357374)
28. Kersh, E. N., Kersh, G. J. & Allen, P. M. Partially phosphorylated T cell receptor ? molecules can inhibit T cell activation. J. Exp. Med. 190, 1627-1636 (1999). (Pubitemid 30002344)
29. Cahalan, M. D. & Chandy, K. G. The functional network of ion channels in T lymphocytes. Immunol. Rev. 231, 59-87 (2009).
30. Aivazian, D. & Stern, L. J. Phosphorylation of T cell receptor is regulated by a lipid dependent folding transition. Nat. Struct. Biol. 7, 1023-1026 (2000).
31. Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3 εcytoplasmic tyrosine-based motif. Cell 135, 702-713 (2008).
32. Sun, Z. J., Kim, K. S., Wagner, G. & Reinherz, E. L. Mechanisms contributing to T cell receptor signaling and assembly revealed by the solution structure of an ectodomain fragment of the CD3 εγheterodimer. Cell 105, 913-923 (2001). (Pubitemid 32635092)
33. Minguet, S., Swamy, M., Alarcon, B., Luescher, I. F. & Schamel, W. W. Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity 26, 43-54 (2007). (Pubitemid 46109342)
34. Mart í nez-Martin, N. et al. Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3ε. Sci. Signal. 2, ra43 (2009).
35. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82-86 (1998). (Pubitemid 28420234)
36. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221-227 (1999). (Pubitemid 29329988)
37. Dustin, M. L. & Depoil, D. New insights into the T cell synapse from single molecule techniques. Nat. Rev. Immunol. 11, 672-684 (2011).
38. Bunnell, S. C. et al. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J. Cell Biol. 158, 1263-1275 (2002).
39. Manz, B. N., Jackson, B. L., Petit, R. S., Dustin, M. L. & Groves, J. T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters. Proc. Natl. Acad. Sci. USA 108, 9089-9094 (2011).
40. W ü lfi ng, C. et al. Costimulation and endogenous MHC ligands contribute to T cell recognition. Nat. Immunol. 3, 42-47 (2002). (Pubitemid 34065616)
41. Krogsgaard, M. et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238-243 (2005). (Pubitemid 40388057)
42. Kuhns, M. S. et al. Evidence for a functional sidedness to the αβTCR. Proc. Natl. Acad. Sci. USA 107, 5094-5099 (2010).
43. Vidal, K., Daniel, C., Hill, M., Littman, D. R. & Allen, P. M. Differential requirements for CD4 in TCR-ligand interactions. J. Immunol. 163, 4811-4818 (1999). (Pubitemid 29501244)
44. Yachi, P. P., Ampudia, J., Zal, T. & Gascoigne, N. R. Altered peptide ligands induce delayed CD8-T cell receptor interaction-a role for CD8 in distinguishing antigen quality. Immunity 25, 203-211 (2006). (Pubitemid 44224141)
45. Campi, G., Varma, R. & Dustin, M. L. Actin and agonist MHC-peptide complexdependent T cell receptor microclusters as scaffolds for signaling. J. Exp. Med. 202, 1031-1036 (2005).
46. Yokosuka, T. et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat. Immunol. 6, 1253-1262 (2005). (Pubitemid 43045637)
47. Lillemeier, B. F. et al. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat. Immunol. 11, 90-96 (2010).
48. Purbhoo, M. A. et al. Dynamics of subsynaptic vesicles and surface microclusters at the immunological synapse. Sci. Signal. 3, ra36 (2010).
49. Monks, C. R., Kupfer, H., Tamir, I., Barlow, A. & Kupfer, A. Selective modulation of protein kinase C-during T-cell activation. Nature 385, 83-86 (1997). (Pubitemid 27024559)
50. Yokosuka, T. et al. Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters and protein kinase C 0θtranslocation. Immunity 29, 589-601 (2008).
51. Choudhuri, K., Wiseman, D., Brown, M. H., Gould, K. & van der Merwe, P. A. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436, 578-582 (2005). (Pubitemid 41112933)
52. Varma, R., Campi, G., Yokosuka, T., Saito, T. & Dustin, M. L. T cell receptorproximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25, 117-127 (2006). (Pubitemid 44066825)
53. Daniels, M. A. et al. Thymic selection threshold defi ned by compartmentalization of Ras/MAPK signalling. Nature 444, 724-729 (2006). (Pubitemid 44949596)
54. Cemerski, S. et al. The stimulatory potency of T cell antigens is infl uenced by the formation of the immunological synapse. Immunity 26, 345-355 (2007). (Pubitemid 46413903)
55. von Boehmer, H. Unique features of the pre-T-cell receptor-chain: not just a surrogate. Nat. Rev. Immunol. 5, 571-577 (2005). (Pubitemid 40961334)
56. Maillard, I., Fang, T. & Pear, W. S. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu. Rev. Immunol. 23, 945-974 (2005). (Pubitemid 40563190)
57. Rothenberg, E. V., Moore, J. E. & Yui, M. A. Launching the T-cell-lineage developmental programme. Nat. Rev. Immunol. 8, 9-21 (2008).
58. Saint-Ruf, C. et al. Analysis and expression of a cloned pre-T cell receptor gene. Science 266, 1208-1212 (1994). (Pubitemid 24371273)
59. δT cells. Nature 375, 795-798 (1995).
60. Pang, S. S. et al. The structural basis for autonomous dimerization of the pre-T-cell antigen receptor. Nature 467, 844-848 (2010).
61. Borowski, C., Li, X., Aifantis, I., Gounari, F. & von Boehmer, H. Pre-TCR αand TCRαare not interchangeable partners of TCR βduring T lymphocyte development. J. Exp. Med. 199, 607-615 (2004). (Pubitemid 38316428)
62. Ishikawa, E., Miyake, Y., Hara, H., Saito, T. & Yamasaki, S. Germ-line elimination of electric charge on pre-T-cell receptor (TCR) impairs autonomous signaling for-selection and TCR repertoire formation. Proc. Natl. Acad. Sci. USA 107, 19979-19984 (2010).
63. Irving, B. A., Alt, F. W. & Killeen, N. Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 280, 905-908 (1998). (Pubitemid 28215601)
64. Aifantis, I. et al. A critical role for the cytoplasmic tail of pTαin T lymphocyte development. Nat. Immunol. 3, 483-488 (2002). (Pubitemid 34520799)
65. Haks, M. C. et al. Low activation threshold as a mechanism for ligand-independent signaling in pre-T cells. J. Immunol. 170, 2853-2861 (2003). (Pubitemid 36302155)
66. Yamasaki, S. et al. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development. Nat. Immunol. 7, 67-75 (2006). (Pubitemid 41823870)
67. Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Immunity 129, 147-161 (2007).
68. Kisielow, P., Teh, H. S., Bluthmann, H. & von Boehmer, H. Positive selection of antigen-specifi c T cells in thymus by restricting MHC molecules. Nature 335, 730-733 (1988).
69. Teh, H. S. et al. Thymic major histocompatibility complex antigens and the αβT-cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335, 229-233 (1988).
70. Finkel, T. H. et al. The thymus has two functionally distinct populations of immature αβ+ T cells: one population is deleted by ligation of αβTCR. Cell 58, 1047-1054 (1989). (Pubitemid 19238182)
71. Berg, L. J. et al. Antigen/MHC-specifi c T cells are preferentially exported from the thymus in the presence of their MHC ligand. Cell 58, 1035-1046 (1989). (Pubitemid 19238181)
72. Alam, S. M. et al. T-cell-receptor affi nity and thymocyte positive selection. Nature 381, 616-620 (1996). (Pubitemid 26177479)
73. Williams, C. B., Engle, D. L., Kersh, G. J., Michael White, J. & Allen, P. M. A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor-ligand complex. J. Exp. Med. 189, 1531-1544 (1999). (Pubitemid 29240878)
74. Kersh, G. J., Engle, D. L., Williams, C. B. & Allen, P. M. Ligand-specifi c selection of MHC class II-restricted thymocytes in fetal thymic organ culture. J. Immunol. 164, 5675-5682 (2000). (Pubitemid 30389808)
75. Naeher, D. et al. A constant affi nity threshold for T cell tolerance. J. Exp. Med. 204, 2553-2559 (2007). (Pubitemid 350044781)
76. Ignatowicz, L., Kappler, J. & Marrack, P. The repertoire of T cells shaped by a single MHC/peptide ligand. Cell 84, 521-529 (1996). (Pubitemid 26071733)
77. Wang, B. et al. A single peptide-MHC complex positively selects a diverse and specifi c CD8 T cell repertoire. Science 326, 871-874 (2009).
78. Davey, G. M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867-1874 (1998). (Pubitemid 28536774)
79. Pircher, H., Rohrer, U. H., Moskophidis, D., Zinkernagel, R. M. & Hengartner, H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature 351, 482-485 (1991). (Pubitemid 21896624)
80. Werlen, G., Hausmann, B. & Palmer, E. A motif in the αβT-cell receptor controls positive selection by modulating ERK activity. Nature 406, 422-426 (2000). (Pubitemid 30625563)
81. Mariathasan, S. et al. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J. Immunol. 167, 4966-4973 (2001). (Pubitemid 33009727)
82. McNeil, L. K., Starr, T. K. & Hogquist, K. A. A requirement for sustained ERK signaling during thymocyte positive selection in vivo. Proc. Natl. Acad. Sci. USA 102, 13574-13579 (2005). (Pubitemid 41420890)
83. Fu, G. et al. Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nat. Immunol. 10, 848-856 (2009).
84. Johnson, A. L. et al. Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat. Immunol. 10, 831-839 (2009).
85. Lesourne, R. et al. Themis, a T cell-specifi c protein important for late thymocyte development. Nat. Immunol. 10, 840-847 (2009).
86. Singer, A. & Bosselut, R. CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision. Adv. Immunol. 83, 91-131 (2004). (Pubitemid 38657638)
87. Fischer, A. M., Katayama, C. D., Pages, G., Pouyssegur, J. & Hedrick, S. M. The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity 23, 431-443 (2005). (Pubitemid 41443444)
88. Jordan, M. S. et al. Thymic selection of CD4 + CD25 + regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301-306 (2001). (Pubitemid 33706340)
89. Hsieh, C. S., Zheng, Y., Liang, Y., Fontenot, J. D. & Rudensky, A. Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401-410 (2006).
90. Moran, A. E. et al. T cell receptor signal strength in T reg and iNKT cell development demonstrated by a novel fl uorescent reporter mouse. J. Exp. Med. 208, 1279-1289 (2011).
91. Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100-111 (2008).
92. Metzger, T. C. & Anderson, M. S. Control of central and peripheral tolerance by Aire. Immunol. Rev. 241, 89-103 (2011).
93. Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specifi c antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039-1049 (2004). (Pubitemid 39431128)
94. Bommhardt, U., Scheuring, Y., Bickel, C., Zamoyska, R. & Hunig, T. MEK activity regulates negative selection of immature CD4 + CD8 + thymocytes. J. Immunol. 164, 2326-2337 (2000). (Pubitemid 30115459)
95. Mallaun, M., Zenke, G. & Palmer, E. A discrete affi nity-driven elevation of ZAP-70 kinase activity initiates negative selection. J. Recept. Signal Transduct. Res. 30, 430-443 (2010).
96. Filbert, E. L. et al. Kinase suppressor of Ras 1 is required for full ERK activation in thymocytes but not for thymocyte selection. Eur. J. Immunol. 40, 3226-3234 (2010).
97. Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848-862 (2008).
98. Takada, K. & Jameson, S. C. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9, 823-832 (2009).
99. Takeda, S., Rodewald, H. R., Arakawa, H., Bluethmann, H. & Shimizu, T. MHC class II molecules are not required for survival of newly generated CD4 + T cells, but affect their long-term life span. Immunity 5, 217-228 (1996). (Pubitemid 26341365)
100. Tanchot, C., Lemonnier, F. A., Perarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057-2062 (1997). (Pubitemid 27443614)
101. Ernst, B., Lee, D. S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173-181 (1999). (Pubitemid 29428810)
102. Viret, C., Wong, F. S. & Janeway, C. A. Jr. Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10, 559-568 (1999). (Pubitemid 29262658)
103. Goldrath, A. W. & Bevan, M. J. Low-affi nity ligands for the TCR drive proliferation of mature CD8 + T cells in lymphopenic hosts. Immunity 11, 183-190 (1999). (Pubitemid 29428811)
104. Goldrath, A. W., Hogquist, K. A. & Bevan, M. J. CD8 lineage commitment in the absence of CD8. Immunity 6, 633-642 (1997). (Pubitemid 27239354)
105. Kassiotis, G., Zamoyska, R. & Stockinger, B. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J. Exp. Med. 197, 1007-1016 (2003). (Pubitemid 36523198)
106. Kieper, W. C., Burghardt, J. T. & Surh, C. D. A role for TCR affi nity in regulating naive T cell homeostasis. J. Immunol. 172, 40-44 (2004). (Pubitemid 38020453)
107. Tarakhovsky, A. et al. A role for CD5 in TCR-mediated signal transduction and thymocyte selection. Science 269, 535-537 (1995).
108. Smith, K. et al. Sensory adaptation in naive peripheral CD4 T cells. J. Exp. Med. 194, 1253-1261 (2001). (Pubitemid 33055044)
109. Azzam, H. S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301-2311 (1998). (Pubitemid 29028502)
110. Palmer, M. J., Mahajan, V. S., Chen, J., Irvine, D. J. & Lauffenburger, D. A. Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naive CD8 + T cells. Immunol. Cell Biol. 89, 581-594 (2011).
111. Ge, Q., Bai, A., Jones, B., Eisen, H. N. & Chen, J. Competition for self-peptide-MHC complexes and cytokines between naive and memory CD8 + T cells expressing the same or different T cell receptors. Proc. Natl. Acad. Sci. USA 101, 3041-3046 (2004). (Pubitemid 38327731)
112. Park, J. H. et al. ' Coreceptor tuning ' : cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specifi city of the TCR. Nat. Immunol. 8, 1049-1059 (2007).
113. Casrouge, A. et al. Size estimate of the αβTCR repertoire of naive mouse splenocytes. J. Immunol. 164, 5782-5787 (2000). (Pubitemid 30389821)
114. Robins, H. S. et al. Comprehensive assessment of T-cell receptor β-chain diversity inαβT cells. Blood 114, 4099-4107 (2009).
115. Harding, C. V. & Unanue, E. R. Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation. Nature 346, 574-576 (1990).
116. Sykulev, Y., Joo, M., Vturina, I., Tsomides, T. J. & Eisen, H. N. Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 4, 565-571 (1996). (Pubitemid 26233310)
117. Irvine, D. J., Purbhoo, M. A., Krogsgaard, M. & Davis, M. M. Direct observation of ligand recognition by T cells. Nature 419, 845-849 (2002). (Pubitemid 35238571)
118. Luescher, I. F. et al. CD8 modulation of T-cell antigen receptor-ligand interactions on living cytotoxic T lymphocytes. Nature 373, 353-356 (1995).