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  • Antigen-specific adaptive immune responses require the function of both T and B lymphocytes. These cells express multichain cell-surface receptors, T cell receptor (TCR) and immunoglobulin (Ig), respectively, that specifically recognize antigenic determinants or epitopes. While Ig directly binds antigens, TCR recognition requires presentation of short peptide antigens via interaction with the class I or class II molecules encoded in the major histocompatibility complex (MHC). Growth and activation of T cells require a network of potent extrinsic regulatory factors (cytokines) acting through specific receptors and signal transduction pathways. The major role of B cells is to produce specific immunoglobulins or antibodies. T cells exhibit diverse functions, including direct cellular cytotoxicity and production of helper factors for B cells and other immune cells. Given the central role of T lymphocytes in coordination of the immune response, defects affecting T and B cells or T cells alone cause severe combined immunodeficiency (SCID). The hallmark of SCID is severe or repeated infections, especially with opportunistic microorganisms. Other features may frequently accompany immunodeficiency including autoimmune phenomena, hematologic abnormalities, dermatoses, and neoplasia, depending on the specific genetic etiology. SCID results from failure of lymphocytes to develop and mature, from defects in MHC expression, and from interruption of signals required for growth and activation. Abnormalities restricted to T cell activation and/or apoptosis account for other genetic defects in T cells with less profound immunodeficiency.

  • DNA rearrangement of the immunoglobulin and T cell receptor loci to generate the repertoire of antigen-specific receptors is a critical developmental checkpoint in both B cells and T cells. Rearrangement occurs by a unique site-specific recombination mechanism acting on signal sequences flanking the receptor loci. The process of receptor exon rearrangement is called V(D)J recombination. At least two lymphocyte-specific proteins, recombination-activating genes 1 and 2 (RAG1 and RAG2), as well as several proteins with broader functions in the repair of double-strand breaks (DSB) in DNA mediate V(D)J recombination. Failure of V(D)J recombination leads to developmental blocks in antigen-specific cell surface receptor expression and consequent failure of both T cell and B cell development (T−B−SCID). Mutations in both RAG1 and RAG2 have been associated with TB SCID. Allelic heterogeneity in RAG1 and RAG2 mutations accounts for the milder phenotype of Omenn syndrome (OS). While not directly impairing the process of TCR rearrangement, disorders affecting DSB repair or related cell-cycle checkpoints, ataxia-telangiectasia, Bloom syndrome, and Nijmegen breakage syndrome, lead to T cell immune deficiency and multiple aberrant chromosomal rearrangements of TCR. These disorders are accompanied by high risk of neoplasia, especially lymphoma.

  • Signal transduction after ligand interaction by the TCR involves a complex of proteins, the CD3 complex, that recruits other signal transduction components. CD3 is composed of two ε, two ζ, and one each of δ and γ chains. In addition, T cells express either CD4 or CD8 as coreceptors that influence the interaction of TCR with MHC class II or class I, respectively. Mutations in zeta-chain-associated protein kinase (ZAP70), a protein ...

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