Table 1. T-cell signalling proteins and human disease

Signalling protein

Function

Disease associations

Clinical applications

Kinases

Lck

Regulation of T-cell
development and activation

SCID (mice) (Refs 115, 116)

None described

ZAP-70

Regulation of T-cell development and activation

SCID (Refs 119, 120, 121, 122, 123)

None described

Autoimmune arthritis
(Ref. 124)

Possible kinase modulators

Phosphatases

CD45

Activates and inhibits Src kinases

SCID (Refs 125, 126, 127, 128), SLE (Ref. 132), MS (Ref. 130), HIV (Refs 133, 134, 135), multiple myeloma (Ref. 37), Alzheimer's disease (Ref. 38), infantile cholestasis (Ref. 131), allograft rejection (Refs 31, 137, 138)

Treatment of Alzheimer's disease (Refs 38, 46), prevention of transplant rejection (Ref. 47), treatment
of leukaemia patients with
radioactive-labelled anti-CD45
antibodies (Ref. 48)

Required for T-cell development and activation

Lymphocytic proliferation
and autoimmunity (Ref. 141)

PTPN22

Inhibits Lck and ZAP-70

RA, type 1 diabetes, SLE (Refs 146, 147, 148, 149, 150, 151, 152, 153, 154, 155)

Potential PTP activators

E3 ligases

Cbl

E3 ligases in the ubiquitination pathway

Spontaneous lympho-proliferative diseases and autoimmunty (Refs 180, 181, 182, 183, 184, 185, 186, 187)

None described; potential of E3 ligase stimulators to dampen autoimmuntiy

GRAIL

Itch

Cytokines

gc

Regulation of cytokine signalling

SCID (Ref. 108)

Gene therapy for the treatment
of X-SCID (Refs 154, 155)

JAK3

SCID (Refs 111, 112, 113)

Adaptors

LAT

Regulation of T-cell development and function; differentiation and homeostasis of Th1/Th2 cells

Autoimmune disease in mice (Ref. 49), RA in humans (Ref. 160)

None described

SLP-76

Regulation of T-cell development and function

None described

None described

ADAP

Regulation of integrin
clustering and p-SMAC formation

None described

None described

SKAP-55

Regulation of integrin clustering/adhesion

None described

None described

WASP

Cytoskeletal remodelling

WAS (Refs 162, 163, 164, 165, 40) XLN (Ref. 168)

Gene therapy for the treatment of WAS (Refs 169, 170, 171, 172)

SAP

Regulation of immune cell activation

XLP (Refs 67, 175, 176)

Gene therapy for the treatment of XLP (Ref. 175)

Abbreviations: ADAP, adhesion-and degranulation-promoting protein; gc, gamma chain; HIV, human immunodeficiency virus; JAK3, Janus kinase 3; LAT, linker for activation of T cells; MS, multiple sclerosis; PTP, protein tyrosine phosphatase; PTPN22, protein tyrosine phosphatase, non-receptor type 22; RA, rheumatoid arthritis; SAP, SLAM-associated protein; SCID, severe combined immunodeficiency; SKAP-55, Src-family-kinase-associated phosphoprotein of 55 kDa; SLE, systemic lupus erythematosus; SLP-76, SH2-domain-containing leukocyte protein of 76 kDa; SLAM, signalling lymphocyte activation molecule; WAS, Wiscott-Aldrich syndrome; WASP, Wiskott Aldrich syndrome protein; XLP, X-linked lymphoproliferative disorder; ZAP-70, zeta-associated protein-70.

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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, PubMed

111 Park, S.Y. et al. (1995) Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3, 771-782, PubMed

112 Thomis, D.C. et al. (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794-797, PubMed

113 Nosaka, T. et al. (1995) Defective lymphoid development in mice lacking Jak3. Science 270, 800-802, PubMed

115 Molina, T.J. et al. (1992) Profound block in thymocyte development in mice lacking p56lck. Nature 357, 161-164, PubMed

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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, PubMed

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, PubMed

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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, PubMed

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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, PubMed

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, PubMed

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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, PubMed

137 Lazarovits, A.I. et al. (1996) Prevention and reversal of renal allograft rejection by antibody against CD45RB. Nature 380, 717-720, PubMed

138 Sho, M. et al. (2005) Requirements for induction and maintenance of peripheral tolerance in stringent allograft models. Proc Natl Acad Sci U S A 102, 13230-13235, PubMed

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146 Bottini, N. et al. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36, 337-338, PubMed

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, PubMed

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, PubMed

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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, PubMed

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, PubMed

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, PubMed

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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, PubMed

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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, PubMed

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176 Wu, C. et al. (2001) SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat Immunol 2, 410-414, PubMed

180 Mueller, D.L. (2004) E3 ubiquitin ligases as T cell anergy factors. Nat Immunol 5, 883-890, PubMed

181 Bachmaier, K. et al. (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211-216, PubMed

182 Chiang, Y.J. et al. (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216-220, PubMed

183 Yokoi, N. et al. (2002) Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 31, 391-394, PubMed

184 Anandasabapathy, N. et al. (2003) GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18, 535-547, PubMed

185 Soares, L. et al. (2004) Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nat Immunol 5, 45-54, PubMed

186 Heissmeyer, V. et al. (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5, 255-265, PubMed

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, PubMed