Ligand-dependent regulation of T cell development and activation Authors
Cite this article as: Germain, R.N. Immunol Res (2003) 27: 277. doi:10.1385/IR:27:2-3:277 Abstract
+ and CD8 +T lymphocytes develop in the thymus from precursors with diverse clonally distributed receptors, possessing binding sites with negligible, intermediate, or high affinity for self-peptide: major histocompatibility complex (MHC) ligands. Positive-and negative-selection processes acting on this precursor pool yield a peripheral T cell population comprised of cells with receptors (TCR) capable of self-peptide: MHC ligand recognition, but largely depleted of those able to mediate overt self-responsiveness. The Lymphocyte Biology Section of the Laboratory of Immunology studies how self-ligand recognition guides T cell development in the thymus and influences the functionality of naive and activated T cells in the periphery. It also seeks to define the molecular basis for the discrimination between self-ligands and foreign antigens that controls T cell activation to effector function. Finally, it uses a combination of conventional cellular immunological methods, biochemical and biophysical studies, and advanced imaging techniques to visualize, quantitate, and model the various steps in the development of primary and memory T cell immune responses. Key Words T lymphocyte T cell receptor MHC molecule Antigen Thymus CD4 CD8 Signaling Vaccines Autoimmunity Tolerance References
Germain RN: MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994;76:287–299.
Davis MM, Bjorkman PJ: T-cell antigen receptor genes and T-cell recognition. Nature 1988;334: 395–402.
Robey E, Fowlkes BJ: Selective events in T cell development. Annu Rev Immunol 1994;12:675–705.
Garcia KC, Teyton L, Wilson IA: Structural basis of T cell recognition. Annu Rev Immunol 1999;17: 369–397.
Germain RN, Stefanova I: The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu Rev Immunol 1999; 17:467–522.
Lucas B, Stefanova I, Yasutomo K, Dautigny N, Germain RN: Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire. Immunity 1999;10:367–376.
Lucas B, Germain RN: Unex pectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4+ CD8+ thymocyte differentiation. Immunity 1996;5:461–477.
Yasutomo K, Doyle C, Miele L, Fuchs C, Germain RN: The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate. Nature 2000; 404:506–510.
Dorfman JR, Stefanova I, Yasutomo K, Germain RN: CD4+ T cell survival is not directly linked to self-MHC-induced TCR signaling. Nature Immunology 2000;1: 329–335.
Dittel BN, Stefanova I, Germain RN, Janeway CA Jr.: Cross-antagonism of a T cell cloneexpressing two distinct T cell receptors. Immunity 1999;11: 289–298.
Delon J, Kaibuchi K, Germain RN: Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin. Immunity 2001;15: 691–701.
Stoll S, Delon J, Brotz TM, Germain RN: Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 2002;296: 1873–1876.
von Boehmer H, Kisielow P, Kishi H, Scott B, Borgulya P, Teh HS: The expression of CD4 and CD8 accessory molecules on mature T cells is not random but correlates with the specificity of the alpha beta receptor for antigen. Immunol Rev 1989;109:143–151.
Robey EA, Fowlkes BJ, Pardoll DM: Molecular mechanisms for lineage commitment in T cell development. Semin Immunol 1990;2:25–34.
Borgulya P, Kishi H, Müller U, Kirberg J, von Boehmer H: Development of the CD4 and CD8 lineage of T cells: in struction versus selection. Embo J 1991;10:913–918.
Robey EA, Fowlkes BJ, Gordon JW, Kioussis D, von Boehmer H, Ramsdell F, Axel R: Thymicselection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell 1991;64:99–107.
Germain RN: T-cell development and the CD4-CD8 lineage decision. Nature Rev Immunol 2002;2: 309–322.
Lundberg K, Heath W, Köntgen F, Carbone F, Shortman K: Intermediate steps in positive selection: differentiation of CD4
thymocytes into CD4
thymocytes. J Exp Med 1995;181: 1643–1651.
Suzuki H, Punt JA, Granger LG, Singer A: A symmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection. Immunity 1995;2: 413–425.
Itano A, Salmon P, Kioussis D, Tolaini M, Corbella P, Robey E: The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells. J Exp Med 1996; 183:731–741.
Matechak EO, Killeen N, Hedrick SM, Fowlkes BJ: MHC class II-specific T cells can develop in the CD8 lineage when CD4 is absent. Immunity 1996;4:337–347.
Bommhardt U, Cole MS, Tso JY, Zamoyska R: Signa is through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus. Eur J Immunol 1997;27:1152–1163.
Yasutomo K, Lucas B, Germain RN: TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting cell type. J Immunol 2000;165:3015–3022.
Brugnera E, Bhandoola A, Cibotti R, et al.: Coreceptorreversal in the thymus: signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Immunity 2000; 13:59–71.
Lucas B, Germain RN: Opening a window on thymic positive selection: developmental changes in the influence of cosignaling by integrins and CD28 on selection events induced by TCR engagement. J Immunol 2000;165:1889–1895.
Kishimoto H, Cai Z, Brummark A, Jackson MR, Peterson PA, Sprent J: Differing roles for B7 and inter-cellular adhesion molecule-1 in negative selection of thymocytes. J Exp Med 1996;184:531–537.
Page DM: Cutting edge: thymic selection and autoreactivity are regulated by multiple coreceptors involved in T cell activation. J Immunol 1999;163:3577–3581.
van Oers NS, Tao W, Watts JD, Johnson P, Aebersold R, Teh HS: Constitutive tyrosine phosphorylation of the T-cell receptor (TCR) ζ subunit: regulation of TCR-associated protein tyrosine kinase activity by TCR ζ. Mol Cell Biol 1993;13:5771–5780.
van Oers NSC, Killeen N, Weiss A: ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR ζ in murine thymocytes and lymph node T cells. Immunity 1994;1:675–685.
Dorfman JR, Germain RN: MHC-dependent survival of naïve T cells? A complicated answer to a simple question. Microbes and Infection 2002;4:547–554.
Dorfman JR, Stefanova II, Yasutomo K, Germain RN: Response to ‘Class II essential for CD4 survival’. 2001;2:136–137.
Clarke SR, Rudensky AY: Survival and homeostatic proliferation of naive peripheral CD4+ T cells in the absence of self peptide: MHC complexes. J Immunol 2000;165: 2458–2464.
Kirberg J, von Boehmer H, Brocker T, Rodewald HR, Takeda S: Class II essential for CD4 survival. Nat Immunol 2001;2:136–137.
Tanchot C, Lemonnier FA, Perarnau B, Freitas AA, Rocha B: Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 1997;276: 2057–2062.
Polic B, Kunkel D, Scheffold A, Rajewsky K: How αβ T cells deal with induced TCR α ablation. Proc Natl Acad Sci USA 2001;98: 8744–8749.
Wong P, Pamer EG: Cutting edge: antigen-independent CD8 T cell proliferation. J Immunol 2001; 166:5864–5868.
Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P: Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 2000;288:675–678.
Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD: Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8(+) cells but are not required for memory phenotype CD4(+) cells. J Exp Med 2002;195: 1523–1532.
Homann D, Teyton L, Oldstone MB: Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat Med 2001;7: 913–919.
Wulfing C, Sumen C, Sjaastad MD, Wu LC, Dustin ML, Davis MM: Costimulation and endogenous MHC ligands contribute to T cell recognition. Nat Immunol 2002;3: 42–47.
McKeithan TW: Kinetic proof-reading in T-cell receptor signal transduction. Proc Natl Acad Sci USA 1995;92:5042–5046.
Rabinowitz JD, Beeson C, Lyons DS, Davis MM, McConnell HM: Kinetic discrimination in T-cell activation. Proc Natl Acad Sci USA 1996;93:1401–1405.
Bosselut R, Zhang W, Ashe JM, Kopacz JL, Samelson LE, Singer A: Association of the adaptormolecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T cell receptor signal transduction. J Exp Med 1999;190:1517–1526.
Huang CY, Ferrell JE Jr: Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 1996;93: 10,078–10,083.
Delon J, Germain RN: Information transfer at the immunological synapse. Curr Biol 2000;10: R923-R933.
Miller MJ, Wei SH, Parker I, Cahalan MD: Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 2002;296:1869–1873.
Bousso P, Bhakta NR, Lewis RS, Bobey E: Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 2002;296:1876–1880.
Siegel RM, Chan FK, Zacharias DA, et al.: Measurement of molecular interactionse in living cells by fluorescence resonance energy transfer between variants of the green fluorescent protein. Sci STKE 2000;2000:PL1.
Hardy J, Edinger M, Bachmann MH, Negrin RS, Fathman CG, Contag CH: Bioluminescence imaging of lymphocyte trafficking in vivo. Exp Hematol 2001;29:1353–1360.
Wipke BT, Wang Z, Kim J, McCarthy TJ, Allen PM: Dynamic visualization of a joint-specific autoimmune response through positronemission tomography. Nat Immunol 2002;3:366–372.
Louie AY, Huber MM, Ahrens ET, et al.: In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol 2000;18:321–325.
Kitano H: Systems biology: a brief overview. Science 2002;295:1 662–1664.
Germain RN: The art of the probable: system control in the adaptive immune system. Science 2001; 293:240–245.