T-cell signalling and immune system disorders

Expert Reviews in Molecular Medicine

Volumn 7, Issue 29, 2005, Pages

  Wilkinson, Beverley ^a   Downey, Jocelyn S ^a   Rudd, Christopher E ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

Adaptor; Autoimmunity; Immunodeficiency; Kinase; Phosphatase; T cell

Indexed keywords

ADAPTOR PROTEIN; ADENOSINE DEAMINASE; CELL ADHESION MOLECULE; CYTOKINE; GUANINE NUCLEOTIDE BINDING PROTEIN; INTERLEUKIN 2; JANUS KINASE; LAT PROTEIN; PHOSPHATASE; PROTEIN KINASE LCK; PROTEIN KINASE ZAP 70; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE PHOSPHATASE; RAG1 PROTEIN; RAG2 PROTEIN; SIGNALING LYMPHOCYTE ACTIVATION MOLECULE ASSOCIATED PROTEIN; SMAD PROTEIN; STAT PROTEIN; T LYMPHOCYTE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA RECEPTOR; UBIQUITIN PROTEIN LIGASE E3; WISKOTT ALDRICH SYNDROME PROTEIN; PHOSPHOTRANSFERASE; SIGNAL TRANSDUCING ADAPTOR PROTEIN;

AUTOIMMUNITY; CELL MATURATION; CELLULAR IMMUNITY; CLONAL ANERGY; COMBINED IMMUNODEFICIENCY; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; EFFECTOR CELL; ENTERITIS; HOMEOSTASIS; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOPATHOLOGY; LEUKEMIA; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE FUNCTION; LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MEDIATOR; MEDICAL RESEARCH; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEFICIENCY; PROTEIN FUNCTION; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; T LYMPHOCYTE; UBIQUITINATION; X CHROMOSOME LINKED DISORDER; ANIMAL; IMMUNOLOGY; METABOLISM; MOUSE;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; CYTOKINES; HUMANS; IMMUNE SYSTEM DISEASES; MICE; PHOSPHOTRANSFERASES; PROTEIN-TYROSINE-PHOSPHATASE; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 31044438230     PISSN: 14623994     EISSN: None     Source Type: Journal    
DOI: 10.1017/S1462399405010264     Document Type: Review

References (217)

1. O'Garra, A. and Arai, N. (2000) The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol 10, 542-550,
2. Raja, A. (2004) Immunology of tuberculosis. Indian J Med Res 120, 213-232,
3. Rudd, C.E. et al. (1988) The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc Natl Acad Sci U S A 85, 5190-5194,
4. Veillette, A. et al. (1989) Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p561ck. Nature 338, 257-259,
5. Rudd, C.E. (1990) CD4, CD8 and the TCR-CD3 complex: a novel class of protein-tyrosine kinase receptor. Immunol Today 11, 400-406,
6. Weiss, A. and Littman, D.R. (1994) Signal transduction by lymphocyte antigen receptors. Cell 76, 263-274,
7. Wange, R.L. and Samelson, L.E. (1996) Complex complexes: signaling at the TCR. Immunity 5, 197-205,
8. Lewis, C.M. et al. (2001) Tec kinases: modulators of lymphocyte signaling and development. Curr Opin Immunol 13, 317-325,
9. Rao, A., Luo, C. and Hogan, P.G. (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15, 707-747,
10. Riley, J.L. and June, C.H. (2005) The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood 105, 13-21,
11. Rudd, C.E. and Schneider, H. (2003) Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 3, 544-556,
12. Greenwald, R.J., Freeman, G.J. and Sharpe, A.H. (2005) The B7 family revisited. Annu Rev Immunol 23, 515-548,
13. Mora, A. et al. (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 15, 161-170,
14. Mustelin, T., Vang, T. and Bottini, N. (2005) Protein tyrosine phosphatases and the immune response. Nat Rev Immunol 5, 43-57,
15. Neel, B.G. (1997) Role of phosphatases in lymphocyte activation. Curr Opin Immunol 9, 405-420,
16. Trowbridge, I.S. and Thomas, M.L. (1994) CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu Rev Immunol 12, 85-116,
17. Hermiston, M.L., Xu, Z. and Weiss, A. (2003) CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol 21, 107-137,
18. Saxena, M. et al. (1999) Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J Biol Chem 274, 11693-11700,
19. Cloutier, J.F. and Veillette, A. (1999) Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med 189, 111-121,
20. Gjorloff-Wingren, A. et al. (1999) Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol 29, 3845-3854,
21. Koretzky, G.A. et al. (1990) Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway. Nature 346, 66-68,
22. Kawai, K. et al. (1995) Impaired development of V gamma 3 dendritic epidermal T cells in p561ck protein tyrosine kinase-deficient and CD45 protein tyrosine phosphatase-deficient mice. J Exp Med 181, 345-349,
23. Mustelin, T., Coggeshall, K.M. and Altman, A. (1989) Rapid activation of the T-cell tyrosine protein kinase pp561ck by the CD45 phosphotyrosine phosphatase. Proc Natl Acad Sci U S A 86, 6302-6306,
24. Pingel, S. et al. (1999) The CD45 tyrosine phosphatase regulates CD3-induced signal transduction and T cell development in recombinase-deficient mice: restoration of pre-TCR function by active p56(lck). Eur J Immunol 29, 2376-2384,
25. Seavitt, J.R. et al. (1999) Expression of the p56(Lck) Y505F mutation in CD45-deficient mice rescues thymocyte development. Mol Cell Biol 19, 4200-4208,
26. Kawabuchi, M. et al. (2000) Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999-1003,
27. Brdicka, T. et al. (2000) Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation. J Exp Med 191, 1591-1604,
28. D'Oro, U. and Ashwell, J.D. (1999) Cutting edge: the CD45 tyrosine phosphatase is an inhibitor of Lck activity in thymocytes. J Immunol 162, 1879-1883,
29. Shenoi, H. et al. (1999) Regulation of integrin-mediated T cell adhesion by the transmembrane protein tyrosine phosphatase CD45. J Immunol 162, 7120-7127,
30. Baker, M. et al. (2000) Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant 1ck mice. Embo J 19, 4644-4654,
31. Fecteau, S. et al. (2001) CTLA-4 up-regulation plays a role in tolerance mediated by CD45. Nat Immunol 2, 58-63,
32. Irie-Sasaki, J. et al. (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349-354,
33. Johnson, K.G. et al. (2000) A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation. Proc Natl Acad Sci U S A 97, 10138-10143,
34. Majeti, R. et al. (1998) Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279, 88-91,
35. Samelson, L.E. (1999) Adaptor proteins and T-cell antigen receptor signaling. Prog Biophys Mol Biol 71, 393-403,
36. Rudd, C.E. (1999) Adaptors and molecular scaffolds in immune cell signaling. Cell 96, 5-8,
37. Koretzky, G.A. and Myung, P.S. (2001) Positive and negative regulation of T-cell activation by adaptor proteins. Nat Rev Immunol 1, 95-107,
38. Zhang, W. et al. (1998) LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92,
39. Weber, J.R. et al. (1998) Molecular cloning of the cDNA encoding pp36, a tyrosine-phosphorylated adaptor protein selectively expressed by T cells and natural killer cells. J Exp Med 187, 1157-1161,
40. Badour, K., Zhang, J. and Siminovitch, K.A. (2004) involvement of the Wiskott-Aldrich syndrome protein and other actin regulatory adaptors in T cell activation. Semin Immunol 16, 395-407,
41. Raab, M. et al. (1997) Regulation of Vav-SLP-76 binding by ZAP-70 and its relevance to TCR zeta/CD3 induction of interleukin-2. Immunity 6, 155-164,
42. Wardenburg, J.B. et al. (1996) Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem 271, 19641-19644,
43. Zhang, W., Trible, R.P. and Samelson, L.E. (1998) LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239-246,
44. Zhang, W. et al. (1999) Essential role of LAT in T cell development. Immunity 10, 323-332,
45. Finco, T.S. et al. (1998) LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity 9, 617-626,
46. Zhang, W. et al. (1999) Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line. Int Immunol 11, 943-950.
47. Lin, J. and Weiss, A. (2001) Identification of the minimal tyrosine residues required for linker for activation of T cell function. J Biol Chem 276, 29588-29595,
48. Paz, P.E. et al. (2001) Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells. Biochem J 356, 461-471,
49. Sommers, C.L. et al. (2002) A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040-2043,
50. Aguado, E. et al. (2002) Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296, 2036-2040,
51. Jackman, J.K. et al. (1995) Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotein associated with Grb2 in T cells. J Biol Chem 270, 7029-7032,
52. Berry, D.M. et al. (2002) A high-affinity Arg-X-X-Lys SH3 binding motif confers specificity for the interaction between Gads and SLP-76 in T cell signaling. Curr Biol 12, 1336-1341,
53. Onodera, H. et al. (1996) Differential regulation of activation-induced tyrosine phosphorylation and recruitment of SLP-76 to Vav by distinct isoforms of the CD45 protein-tyrosine phosphatase. J Biol Chem 271, 22225-22230,
54. Tuosto, L., Michel, F. and Acuto, O. (1996) p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells. J Exp Med 184, 1161-1166,
55. Bubeck Wardenburg, J. et al. (1998) Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9, 607-616,
56. Bunnell, S.C. et al. (2000) Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. J Biol Chem 275, 2219-2230,
57. Su, Y.W. et al. (1999) Interaction of SLP adaptors with the SH2 domain of Tec family kinases. Eur J Immunol 29, 3702-3711,
58. Zeng, R. et al. (2003) SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site. J Immunol 171, 1360-1368,
59. Yablonski, D. et al. (1998) Uncoupling of nonreceptor tyrosine kinases from PLC-gamma1 in an SLP-76-deficient T cell. Science 281, 413-416,
60. Schneider, H. et al. (2000) Resting lymphocyte kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in the cooperative activation of interleukin-2 transcription in T-cells. J Biol Chem 275, 3835-3840,
61. Clements, J.L. et al. (1998) Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281, 416-419,
62. Pivniouk, V. et al. (1998) Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 94, 229-238,
63. Kumar, L. et al. (2002) Differential role of SLP-76 domains in T cell development and function. Proc Natl Acad Sci U S A 99, 884-889,
64. Myung P.S. et al. (2001) Differential requirement for SLP-76 domains in T cell development and function. Immunity 15, 1011-1026,
65. da Silva, A.J. et al. (1997) Cloning of a novel T-cell protein FYB that binds FYN and SH2-domain-containing leukocyte protein 76 and modulates interleukin 2 production. Proc Natl Acad Sci U S A 94, 7493-7498,
66. Musci, M.A. et al. (1997) Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinases. J Biol Chem 272, 11674-11677,
67. Sayos, J. et al. (1998) The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462-469,
68. Coffey, A.J. et al. (1998) Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 20, 129-135,
69. Latour, S. and Veillette, A. (2003) Molecular and immunological basis of X-linked lymphoproliferative disease. Immunol Rev 192, 212-224,
70. Chan, B. et al. (2003) SAP couples Fyn to SLAM immune receptors. Nat Cell Biol 5, 155-160,
71. Latour, S. et al. (2001) Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nat Immunol 2, 681-690,
72. Sanzone, S. et al. (2003) SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients. J Biol Chem 278, 29593-29599,
73. Simarro, M. et al. (2004) SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9. Int Immunol 16, 727-736,
74. Bustelo, X.R. (2000) Regulatory and signaling properties of the Vav family. Mol Cell Biol 20, 1461-1477,
75. Barda-Saad, M. et al. (2005) Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. Nat Immunol 6, 80-89,
76. Machesky, L.M. and Insall, R.H. (1998) Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr Biol 8, 1347-1356,
77. Higgs, H.N. and Pollard, T.D. (2000) Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. J Cell. Biol 150, 1311-1320,
78. Zhang, J. et al. (1999) Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J Exp Med 190, 1329-1342,
79. Kim, A.S. et al. (2000) Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. Nature 404, 151-158,
80. Holsinger, L.J. et al. (1998) Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction. Curr Biol 8, 563-572,
81. Fischer, K.D. et al. (1998) Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr Biol 8, 554-562,
82. Hogg, N. et al. (2003) T-cell integrins: more than just sticking points. J Cell Sci 116, 4695-4705,
83. Shimaoka, M. et al. (2003) Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112, 99-111,
84. Monks, C.R. et al. (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82-86,
85. Dustin, M.L. and Shaw, A.S. (1999) Costimulation: building an immunological synapse. Science 283, 649-650,
86. Krawczyk, C. et al. (2002) Vav1 controls integrin clustering and MHC/ peptide-specific cell adhesion to antigen-presenting cells. Immunity 16, 331-343,
87. Bos, J.L. (2005) Linking Rap to cell adhesion. Curr Opin Cell Biol 17, 123-128,
88. Katagiri, K. et al. (2002) Rap1 functions as a key regulator of T-cell and antigen-presenting cell interactions and modulates T-cell responses. Mol Cell Biol 22, 1001-1015,
89. Veale, M. et al. (1999) Novel isoform of lymphoid adaptor FYN-T-binding protein (FYB-130) interacts with SLP-76 and up-regulates interleukin 2 production. J Biol Chem 274, 28427-28435,
90. Geng, L., Raab, M. and Rudd, C.E. (1999) Cutting edge: SLP-76 cooperativity with FYB/FYN-T in the Up-regulation of TCR-driven IL-2 transcription requires SLP-76 binding to FYB at Tyr595 and Tyr651. J Immunol 163, 5753-5757,
91. Raab, M. et al. (1999) FYN-T-FYB-SLP-76 interactions define a T-cell receptor zeta/CD3-mediated tyrosine phosphorylation pathway that up-regulates interleukin 2 transcription in T-cells. J Biol Chem 274, 21170-21179,
92. da Silva, A.J. et al. (1997) Biochemical analysis of p120/130: a protein-tyrosine kinase substrate restricted to T and myeloid cells. J Immunol 158, 2007-2016,
93. Geng, L. et al. (2001) Adaptor FYB (Fyn-binding protein) regulates integrin-mediated adhesion and mediator release: differential involvement of the FYB SH3 domain. Proc Natl Acad Sci USA 98, 11527-11532,
94. Geng, L. and Rudd, C. (2001) Adaptor ADAP (adhesion- and degranulation-promoting adaptor protein) regulates beta1 integrin clustering on mast cells. Biochem Biophys Res Commun 289, 1135-1140,
95. Peterson, E.J. et al. (2001) Coupling of the TCR to integrin activation by Slap-130/Fyb. Science 293, 2263-2265,
96. Griffiths, E.K. et al. (2001) Positive regulation of T cell activation and integrin adhesion by the adapter Fyb/Slap. Science 293, 2260-2263,
97. Wang, H. et al. (2004) ADAP-SLP-76 binding differentially regulates supramolecular activation cluster (SMAC) formation relative to T cell-APC conjugation. J Exp Med 200, 1063-1074,
98. Krause, M. et al. (2000) Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton. J Cell Biol 149, 181-194,
99. Liu, J. et al. (1998) FYB (FYN binding protein) serves as a binding partner for lymphoid protein and FYN kinase substrate SKAP55 and a SKAP55-related protein in T cells. Proc Natl Acad Sci USA 95, 8779-8784,
100. Marie-Cardine, A. et al. (1997) Molecular cloning of SKAP55, a novel protein that associates with the protein tyrosine kinase p59fyn in human T-lymphocytes. J Biol Chem 272, 16077-16080,
101. Wang, H. et al. (2003) SKAP-55 regulates integrin adhesion and formation of T cell-APC conjugates. Nat Immunol 4, 366-374,
102. Jo, E.K., Wang, H. and Rudd, C.E. (2005) An essential role for SKAP-55 in LFA-1 clustering on T cells that cannot be substituted by SKAP-55R. J Exp Med 201, 1733-1739,
103. Bear, J.E. et al. (2002) Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility. Cell 109, 509-521,
104. Jacobelli, J. et al. (2004) A single class II myosin modulates T cell motility and stopping, but not synapse formation. Nat Immunol 5, 531-538,
105. Ihle, J.N. and Kerr, I.M. (1995) Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet 11, 69-74,
106. Kawamura, M. et al. (1994) Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci USA 91, 6374-6378,
107. Gurniak, C.B. and Berg, L.J. (1996) Murine JAK3 is preferentially expressed in hematopoietic tissues and lymphocyte precursor cells. Blood 87, 3151-3160,
108. Russell, S.M. et al. (1994) Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266, 1042-1045,
109. Leonard, W.J. (1994) The defective gene in X-linked severe combined immunodeficiency encodes a shared interleukin receptor subunit: implications for cytokine pleiotropy and redundancy. Curr Opin Immunol 6, 631-635,
110. Asao, H. et al. (2001) Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol 167, 1-5,
111. Park, S.Y. et al. (1995) Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3, 771-782,
112. Thomis, D.C. et al. (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794-797,
113. Nosaka, T. et al. (1995) Defective lymphoid development in mice lacking Jak3. Science 270, 800-802,
114. Reguly, T. and Wrana, J.L. (2003) In or out? The dynamics of Smad nucleocytoplasmic shuttling. Trends Cell Biol 13, 216-220,
115. Molina, T.J. et al. (1992) Profound block in thymocyte development in mice lacking p56lck. Nature 357, 161-164,
116. Levin, S.D. et al. (1993) The protein tyrosine kinase p56lck regulates thymocyte development independently of its interaction with CD4 and CD8 coreceptors [corrected]. J Exp Med 178, 245-255,
117. Fischer, A. (2000) Severe combined immunodeficiencies (SCID). Clin Exp Immunol 122, 143-149,
118. Boulanger, M.J. and Garcia, K.C. (2004) Shared cytokine signaling receptors: structural insights from the gp130 system. Adv Protein Chem 68, 107-146,
119. Elder, M.E. et al. (1994) Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264, 1596-1599,
120. Arpaia, E. et al. (1994) Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell 76, 947-958,
121. Chan, A.C. et al. (1994) ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264, 1599-1601,
122. Gelfand, E.W. et al. (1995) Absence of ZAP-70 prevents signaling through the antigen receptor on peripheral blood T cells but not on thymocytes. J Exp Med 182,1057-1065,
123. Toyabe, S. et al. (2001) Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling. Immunology 103, 164-171,
124. Sakaguchi, N. et al. (2003) Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454-460,
125. Kishihara, K. et al. (1993) Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74, 143-156,
126. Kung, C. et al. (2000) Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med 6, 343-345,
127. Tchilian, E.Z. et al. (2001) A deletion in the gene encoding the CD45 antigen in a patient with SCID. J Immunol 166,1308-1313,
128. Cale, C.M. et al. (1997) Severe combined immunodeficiency with abnormalities in expression of the common leucocyte antigen, CD45. Arch Dis Child 76, 163-164,
129. Jacobsen, M. et al. (2000) A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat Genet 26, 495-499,
130. Tan, J. et al. (2000) CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase. J Neurosci 20, 7587-7594,
131. Socha, P. et al. (2001) Deficiency of the expression of CD45RA isoform of CD45 common leukocyte antigen in CD4+ T lymphocytes in children with infantile cholestasis. Immunol Lett 75, 179-184,
132. Neidhart, M. et al. (1996) CD45 isoforms expression on CD4+ and CD8+ peripheral blood T-lymphocytes is related to auto-immune processes and hematological manifestations in systemic lupus erythematosus. Schweiz Med Wochenschr 126, 1922-1925,
133. Spina, C.A., Prince, H.E. and Richman, D.D. (1997) Preferential replication of HIV-1 in the CD45RO memory cell subset of primary CD4 lymphocytes in vitro. J Clin Invest 99, 1774-1785,
134. Helbert, M.R. et al. (1997) HIV infection of CD45RA+ and CD45RO+ CD4+ T cells. Clin Exp Immunol 107, 300-305,
135. Barbeau, B. et al. (2001) Negative regulation of the NFAT1 factor by CD45: implication in HIV-1 long terminal repeat activation. J Immunol 167, 2700-2713,
136. Tan, J., Town, T. and Mullan, M. (2000) CD45 inhibits CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK pathway. J Biol Chem 275, 37224-37231,
137. Lazarovits, A.I. et al. (1996) Prevention and reversal of renal allograft rejection by antibody against CD45RB. Nature 380, 717-720,
138. Sho, M. et al. (2005) Requirements for induction and maintenance of peripheral tolerance in stringent allograft models. Proc Natl Acad Sci USA 102, 13230-13235,
139. Countouriotis, A., Moore, T.B. and Sakamoto, K.M. (2002) Cell surface antigen and molecular targeting in the treatment of hematologic malignancies. Stem Cells 20, 215-229,
140. Lee, K. and Burke, T.R., Jr. (2003) CD45 protein-tyrosine phosphatase inhibitor development. Curr Top Med Chem 3, 797-807,
141. Majeti, R. et al. (2000) An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103, 1059-1070,
142. Nam, H.J. et al. (2005) Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J Exp Med 201, 441-452,
143. Takeuchi, T. et al. (1997) Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 109, 20-26,
144. Long, E.O. (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17, 875-904,
145. Stefanova, I. et al. (2003) TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4,248-254,
146. Bottini, N. et al. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36, 337-338,
147. Begovich, A.B. et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75, 330-337,
148. Smyth, D. et al. (2004) Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53, 3020-3023,
149. Onengut-Gumuscu, S. et al. (2004) A functional polymorphism. (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families. Genes Immun 5, 678-680,
150. Ladner, M.B. et al. (2005) Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum Immunol 66, 60-64,
151. Kyogoku, C. et al. (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 75, 504-507,
152. Velaga, M.R. et al. (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J Clin Endocrinol Metab 89, 5862-5865,
153. Criswell, L.A. et al. (2005) Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76, 561-571,
154. Orozco, G. et al. (2005) Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 52, 219-224,
155. Lee, A.T. et al. (2005) The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status. Genes Immun 6, 129-133,
156. Begovich, A.B. et al. (2005) The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 76, 184-187,
157. Hasegawa, K. et al. (2004) PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303, 685-689,
158. Solimena, M. et al. (1996) ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. Embo J 15, 2102-2114,
159. Kawasaki, E., Hutton, J.C. and Eisenbarth, G.S. (1996) Molecular cloning and characterization of the human transmembrane protein tyrosine phosphatase homologue, phogrin, an autoantigen of type 1 diabetes. Biochem Biophys Res Commun 227, 440-447,
160. Malissen B., Aguado, E. and Malissen, M. (2005) Role of the LAT adaptor in T-cell development and Th2 differentiation. Adv Immunol 87, 1-25,
161. Snapper, S.B. and Rosen, F.S. (1999) The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol 17, 905-929,
162. MacCarthy-Morrogh, L. et al. (1998) Absence of expression of the Wiskott-Aldrich syndrome protein in peripheral blood cells of Wiskott-Aldrich syndrome patients. Clin Immunol Immunopathol 88, 22-27,
163. Lemahieu, V., Gastier, J.M. and Francke, U. (1999) Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat 14, 54-66,
164. Shcherbina, A., Rosen, F.S. and Remold-O'Donnell, E. (1999) WASP levels in platelets and lymphocytes of wiskott-aldrich syndrome patients correlate with cell dysfunction. J Immunol 163, 6314-6320,
165. Snapper, S.B. et al. (1998) Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9, 81-91,
166. Badour, K. et al. (2003) The Wiskott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity 18, 141-154,
167. Badour, K. et al. (2004) Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J Exp Med 199, 99-112,
168. Devriendt, K. et al. (2001) Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 27, 313-317,
169. Thrasher, A.J. (2002) WASp in immune-system organization and function. Nat Rev Immunol 2, 635-646,
170. Wada, T. et al. (2002) Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction. Hum Gene Ther 13, 1039-1046,
171. Strom, T.S. et al. (2003) Functional correction of T cells derived from patients with the Wiskott-Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein. Gene Ther 10, 803-809,
172. Klein, C. et al. (2003) Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood 101, 2159-2166,
173. Nichols, K.E. et al. (1998) Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci USA 95, 13765-13770,
174. Howie, D. et al. (2000) The gene defective in X-linked lymphoproliferative disease controls T cell dependent immune surveillance against Epstein-Barr virus. Curr Opin immunol 12, 474-478,
175. Nelson, D.L. and Terhorst, C. (2000) X-linked lymphoproliferative syndrome. Clin Exp Immunol 122, 291-295,
176. Wu, C. et al. (2001) SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat Immunol 2, 410-414,
177. Nakamura, H. et al. (2001) Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome. J Immunol 167, 2657-2665,
178. Sharifi, R. et al. (2004) SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease. Blood 103, 3821-3827,
179. Weissman, A.M. (2001) Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2, 169-178,
180. Mueller, D.L. (2004) E3 ubiquitin ligases as T cell anergy factors. Nat Immunol 5, 883-890,
181. Bachmaier, K. et al. (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211-216,
182. Chiang, Y.J. et al. (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216-220,
183. Yokoi, N. et al. (2002) Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 31, 391-394,
184. Anandasabapathy, N. et al. (2003) GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcriptional is expressed in anergic CD4+ T cells. Immunity 18, 535-547,
185. Soares, L. et al. (2004) Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nat Immunol 5, 45-54,
186. Heissmeyer, V. et al. (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5, 255-265,
187. Fang D. et al. (2002) Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 3, 281-287,
188. Buckley, R.H. et al. (1997) Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr 130, 378-387,
189. Buckley, R.H. et al. (1999) Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 340, 508-516,
190. Haddad, E. et al. (1998) Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients. Blood 91, 3646-3653,
191. Patel, D.D. et al. (2000) Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 342, 1325-1332,
192. Otsu, M. et al. (2000) Lymphoid development and function in X-linked severe combined immunodeficiency mice after stem cell gene therapy. Mol Ther 1, 145-153,
193. Cavazzana-Calvo, M. et al. (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669-672,
194. Fischer, A., Hacein-Bey, S. and Cavazzana-Calvo, M. (2002) Gene therapy of severe combined immunodeficiencies. Nat Rev Immunol 2, 615-621,
195. O'Shea, J.J. et al. (2004) A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 3, 555-564,
196. Gaspar, H.B. et al. (2004) Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364, 2181-2187,
197. Hacein-Bey-Abina, S. et al. (2002) Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 346, 1185-1193,
198. Hacein-Bey-Abina, S. et al. (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415-419,
199. Hershfield, M.S. (2004) Combined immune deficiencies due to purine enzyme defects. In Immunologic Disorders in Infants and Children (Stiehm, E.R., Ochs, H.D. and Winkelstein, J.A., eds), pp. 480-504, W.B. Saunders, Philadelphia
200. Apasov, S.G. et al. (2001) Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest 108, 131-141,
201. Aiuti, A. et al. (2002) Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 8, 423-425,
202. Aiuti, A. et al. (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410-2413,
203. Gellert, M. (2002) V(D)J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem 71, 101-132,
204. Fugmann, S.D. et al. (2000) The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu Rev Immunol 18, 495-527,
205. Rooney, S., Chaudhuri, J. and Alt, EW. (2004) The role of the non-homologous end-joining pathway in lymphocyte development. Immunol Rev 200, 115-131,
206. de Villartay, J.P. (2002) V(D)J recombination and DNA repair: lessons from human immune deficiencies and other animal models. Curr Opin Allergy Clin Immunol 2, 473-479,
207. Moshous, D. et al. (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177-186,
208. Hahm, K.B. et al. (2001) Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 49, 190-198,
209. Maloy, K.J. and Powrie, F. (2001) Regulatory T cells in the control of immune pathology. Nat Immunol. 2, 816-822,
210. Yang, X. et al. (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. Embo J 18, 1280-1291,
211. Monteleone, G. et al. (2001) Blocking Smad7 restores TGF-betal signaling in chronic inflammatory bowel disease. J Clin Invest 108, 601-609,
212. Schreiber, S., Nikolaus, S. and Hampe, J. (1998) Activation of nuclear factor kappa B inflammatory bowel disease. Gut 42, 477-484,
213. Stoll, M. et al. (2004) Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet 36, 476-480,
214. Neurath, M.F., Finotto, S. and Glimcher, L.H. (2002) The role of Th1/Th2 polarization in mucosal immunity. Nat Med 8, 567-573,
215. Lippincott-Schwartz, J. and Patterson, G.H. (2003) Development and use of fluorescent protein markers in living cells. Science 300, 87-91,
216. Zimmermann, T., Rietdorf, J. and Pepperkok, R. (2003) Spectral imaging and its applications in live cell microscopy. FEBS Lett 546, 87-92,
217. Eils, R. and Athale, C. (2003) Computational imaging in cell biology. J Cell Biol 161, 477-481,