Defects in TCR Signal Transduction

Many examples of rare immunodeficiency diseases caused by defects in the expression of molecules required for T cell activation and function have been identified, and some have already been discussed in the context of SCID. Biochemical and molecular analyses of affected individuals have revealed mutations in the genes encoding various T cell proteins (see Table 20-5). Examples include impaired TCR complex expression or function caused by mutations in the CD3 e or y genes, defective TCR-mediated signaling caused by mutations in the ZAP70 gene, reduced synthesis of cytokines such as IL-2 and IFN-y (in some cases caused by defects in transcription factors), and lack of expression of IL-2 receptor chains. These defects are often found in only a few isolated cases or in a few families, and the clinical features and severity vary widely. Patients with these abnormalities may have deficiencies predominantly in T cell function or have mixed T cell and B cell immunodeficiencies despite normal or even elevated numbers of blood lymphocytes. We have previously considered the importance of the CD3 complex at the pre-TCR checkpoint, the role of ZAP70 mutations in CD8+ T cell development, and the relevance of ORAI1 and STIM1 in T cell activation, all in the clinical context of SCID. Other syndromes involving the defective activation of mature T cells are considered here.

TABLE 20-5 Defects in T Cell Activation


Functional Deficiencies

Mechanism of Defect

Defects in MHC expression

Bare lymphocyte syndrome

Defective MHC class II expression and deficiency in CD4+ T cells; defective cell-mediated immunity and T-dependent humoral immune responses

Defects in transcription factors regulating MHC class II gene expression, including CIITA, RFXANK, RFX5, and RFXAP

MHC class I deficiency

Decreased MHC class I levels; reduced CD8+ T cells

Mutations in TAP1, TAP2, and TAPASIN

Defective T cell signaling

Proximal TCR signaling defects

Defects in cell-mediated immunity and T-dependent humoral immunity

Mutations in CD3genes, CD45, STIM1, ORAI1

Wiskott-Aldrich syndrome

Defective T cell activation, leukocyte mobility

TCR-dependent actin-cytoskeletal rearrangements are defective because of mutations in WASP

Familial hemophagocytic lymphohistiocytoses

X-linked lymphoproliferative syndrome

Uncontrolled EBV-induced B cell proliferation, uncontrolled macrophage and CTL activation, defective NK cell and CTL function

Mutations in SAP

Perforin deficiencies

Uncontrolled macrophage and CTL activation, defective NK cell and CTL function

Mutations in PERFORIN

Granule fusion

Uncontrolled macrophage and CTL activation, defective NK cell and CTL function

Defective cytotoxic granule exocytosis; mutations in RAB27A, MUNC13-4, SYNTAXIN, AP3 (and in LYST in Chédiak-Higashi syndrome—see Table 20-2)

AP3, adaptor-related protein complex 3; LYST, lysosomal trafficking regulator protein; SAP, SLAM-associated protein; TAP, transporter associated with antigen processing; WASP, Wiskott-Aldrich syndrome protein.

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