Cytokines such as interleukin (IL)-2, IL-4, IL-12 and others dramatically influence the immune response and therefore understanding the molecular basis of cytokine signal transduction should provide important insights into lymphocyte activation. To this end, we cloned a protein tyrosine kinase, JAK3 that is a critical element in signaling via the subfamiy of cytokine (IL-2, IL-4, IL-7, IL-9, and IL15) receptors that use the common gamma chain (gamma-c). The discovery that mutations of gamma-c are the molecular basis of X-linked severe combined immunodeficiency(X-SCID), let us map the JAK3 locus to chromosome 19 and then to identify patients with autosomal SCID that is due to mutations of JAK3 itself indicating that JAK3 and its function are critical in the development of the immune system. We went on to furtuer characterize the consequence of JAK3 deficiency in terms of signaling by different gamma-c using cytokines. Specifically, we showed that IL-2 signaling is severely impaired by JAK3 deficiency whereas IL-4 is only partially impaired. These findings were confirmed by analyzing signaling in cells from patients with XSCID, i.e., gamma-c deficiency; together they indicate the existence of a gamma-c/JAK3 independent signaling pathway for IL-4, a finding that may have important implications in the pathogenesis of these diseases. We further showed that these cellular defects can be corrected retroviral gene transduction. We also sequenced the JAK3 gene to facilitate the identification of other JAK3 deficient patients. We have also investigated IL-12 signal transduction and demonstrated that it involves the kinases JAK2 and TYK2 and the STAT4 transcription factor. We also have shown that IL-12 induces serine as well as tyrosine phosphorylation of STAT4 and this appears to be important for transactivation. It is hoped that understanding the precise mechanisms involved in cytokine signaling will provide avenues for the development of novels agents that can regulate the immune response in a therapeutically desirable manner.
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