Defects in one of four functionally related genes causes T-B+SCID. X-linked SCID, which is the commonest form, is due to a mutation of the gene encoding the IL-2 receptor γ-chain, which is the signal-transducing chain common to the receptors for six cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21). The absence of responses to these cytokines causes defects in a broad range of T- and B-cell functions. IL-7 is required for early stages of T-cell development. Lack of response to this cytokine results in T lymphopenia. IL-15 is required for NK-cell development and its lack results in the failure of NK-cell development. Signal transduction through the aforementioned cytokine receptors involves the interaction of the common γ chain with the tyrosine kinase JAK3. This explains why mutation of the JAK3 gene result in an autosomal recessive form of SCID, with a phenotype similar to X-linked SCID. Mutations of the α chain of IL-2 or IL-7 receptors result in two rare forms of SCID.