Cytokine receptor γc chain/Jak3 mediated signal transduction and analysis of immunodeficiecy by dysfunction of the γc chain/Jak3

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We identified and have characterized the interleukin 2 receptor γ chain (IL-2Rγ ), of which mutations cause Human X-linked severe combined immunodeficiency disease ( XSCID ), a disease that occurs in as many as 50 % of patients with primary SCID. It was found that mutations of Jak3, which is associated with and mediates the down stream signal transduction from the γ chain, also caused autosomal recessive SCID. Thus, we considered the possibility that there is the novel gene related to SCID down stream of Jak3 and then originally identified novel Jak3 substrates including STAM. In this study, using the gene targeting and transgenic mice we analyzed the in vivo function of the molecules to determine its involvement in the signal transduction pathway from γ chain /Jak3.( 1 ) Double deficient mice, lacking both STAM1 and STAM2, were embryonically lethal. To further elucidate the function of STAM in lymphocytes, we established conditionally targeting mice that will lack of both molecules in lymphocytes( 2 ) Hgs knockout ( KO ) mice showed significantly decreased response to stimulation with transforming growth factor-β ( TGF-β ) family molecules.( 3 ) AMSH-deficient mice exhibited postnatal growth, retardation and died between day 19 and 23. The neurons were defect in the subfield of hippocampus of AMSH-deficient mice.( 4 ) The total number of thymocytes were reduced in the transgenic mice expressing Graf40 mutant, whereas it was significantly increased in the double-negative thymocytes subset.