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 T−B− 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 tyrosine kinase that interacts with the ζ chain of CD3, result in a characteristic deficiency of CD8+ T cells. Lck is a src-family protein tyrosine kinase that interacts with CD4. Rare mutations in lck lead to a specific defect in the maturation of CD4+ T cells.

Recognition of antigenic peptides by TCR requires presentation of the peptide by either class I or class II MHC proteins. MHC cell surface expression depends on intracellular association with processed peptide antigens delivered to the lumen of the endoplasmic reticulum by the TAP peptide transporter. The peptide transporter is composed of transporter, ATP-binding cassette 1 (TAP1) and transporter, ATP-binding cassette 2 (TAP2) proteins. Failure of proper cell surface expression of either class I or class II proteins or both results in severe humoral and cellular immune deficiency. MHC class I deficiencies are rare disorders with apparent locus heterogeneity. MHC class I deficiency can result from mutations in either TAP1 or TAP2, although the molecular basis for the condition is otherwise unknown. MHC class II deficiency is also heterogeneous with five complementation groups currently identified. MHC class II deficiencies all result from defects in the transcriptional regulation of the class II gene family. Complementation group A results from mutations in the transcription factor MHC class II transactivator (MHC2TA). Complementation groups B, C, and D result from mutations in subunits of the regulatory factor X (RFX) DNA-binding complex (RFX, ankyrin repeat containing (RFXANK), RFX5, and RFX-associated protein (RFXAP), respectively) that regulates MHC class II transcription.

Proper regulation of immune responsiveness requires selection of the T cell repertoire and control of clonal T cell proliferation. Abnormal regulation of T cells underlies rare autoimmune disorders characterized by poorly controlled T cell proliferation and immunodeficiency. Defects in T cell apoptosis caused by mutations in either Fas (tumor necrosis factor receptor superfamily, member 6; (TNFRSF6) or caspase 10 lead to autoimmune lymphoproliferative syndrome (ALPS). A rare form of autoimmunity—autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED)—is caused by mutations in a novel lymphoid lineage transcription factor, autoimmune regulator (AIRE). Finally, autosomal recessive autoimmune syndrome can be caused by mutation in the IL2Rα gene.

T cell growth and maturation require the activities of multiple cytokines. The hematopoietin family of cytokines is particularly important as evidenced by the severe phenotype associated with defects in receptors and signaling. The most common form of SCID is the X-linked SCID (XSCID) caused by mutations in a subunit, γc, of IL2 receptor (IL2Rγ, IL2RG). This subunit is shared with receptors for IL4, IL7, IL9, and IL15. Defects in the function of the IL7-dependent axis may be particularly important in XSCID, because rare patients with mutations in the α chain of the IL7 receptor (IL7Rα, IL7RA) component also exhibit SCID. This subfamily of receptors interacts with the protein tyrosine kinases JAK1 and JAK3 that play critical roles in cytokine receptor signal transduction. The γc subunit specifically interacts with JAK3. One form of autosomal recessive SCID results from JAK3 mutations. Interferons constitute another cytokine family. Interferon γ is particularly important in the induction of class II MHC expression. Defects in the interferon γ receptor lead to increased susceptibility to mycobacterial infections.

Wiskott-Aldrich syndrome (WAS) is an X-linked immune deficiency affecting antigen-specific T cell proliferation. Failure of antibody responses to polysaccharide antigens is a unique characteristic. In addition to the immune deficiency, the classic clinical features include eczema and thrombocytopenia. Patients also commonly exhibit autoimmune phenomena and have increased risk for malignancy. The disorder results from mutations in a novel X-linked gene, WAS, that encodes the Wiskott-Aldrich syndrome protein (WASP). WASP contains several peptide motifs that point to a role in coordinating signal transduction and cytoplasmic actin movements. WAS is allelic to the rare X-linked thrombocytopenia (XLT).

A variety of miscellaneous cellular immune deficiencies remain to be classified based on molecular pathology. These include an autosomal recessive SCID unique to the Athabascan people, reticular dysgenesis, and cartilage hair hypoplasia (CHH). In addition, two inborn errors of purine metabolism, adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency, are responsible for about 15 percent of SCID. Immune deficiency with centromeric instability and dysmorphic facies (ICF) syndrome was recently found to be due to mutations in DNA methyltransferase 3B (DNMT3B), a component necessary for maintenance of chromatin conformation.