Cytokine receptor γc chain mediated signal transduction and analysis of immunodeficiency by dysfunction of the γc chain

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The interleukin 2 receptor γ chain (IL-2Rγ ), which we previously cloned, is known to be a causative gene for human X-linked severe combined immunodeficiency (X-SCID). X-SCID is a disease that occurs in as many as 50% of patients with primary SCID, and is characterized with profound defect of T and NK cells and impairment of B cell differentiation. The IL-2Rγ is shared among the receptors for several cytokines, and called the common γ(γc) chain. The cytoplasmic domain of the γc chain is associated with Jak3 tyrosine kinase, of which mutantions also cause an autosomal recessive SCID, Jak3-SCID. These observations suggest that the γc/Jak3 signaling pathway is indispensable for development of T, NK and B cells. We thus hypothesized that molecules involved in the γc/Jak3 signaling pathway may include causative gene products for SCID. In this context, we have identified STAM1, which is associated with Jak3 and Jak2, and involved in signaling for cell proliferation and c-myc induction mediated by IL-2 and GM-CSF. STAM1 knockout mice were born and developed normally, but their body weights decreased gradually after 5 weeks of age, and were below 60-70% of those of normal mice. 90% of the mice died before 16 weeks of age. Until 4 weeks of age, STAM1 knockout mice were normal clinically, but histopathologically they showed an abnormality in the CA3 region of the hippocampus. On the other hand, we molecularly cloned a STAM1 homologous molecule named STAM2, and revealed that STAM2 has similar in vitro functions to STAM1, suggesting that STAM1 may be compensated by STAM2 in the STAM1 knockout mice. We have also developed STAM2 knockout mice, which show normal growth and no abnormal features so far. We are now attempting to establish double KO mice for STAM1 and STAM2 to examine their possible functional relationship.