IL-7 is a key cytokine in the immune system, essential for normal development of B cells and T cells. Mice with the IL-7 receptor deleted lack B and T cells. Some humans with SCID (severe combined immunodeficiency disease) also have mutation of their IL-7 receptor gene leading to an absence of T cells and greatly impaired B cell production. The IL-7 receptor includes two polypeptides, a gamma chain and an alpha chain. The alpha-chain is unique to the IL-7 receptor while several other cytokines use the same gamma receptor chain as IL-7, including IL-2, IL-4, IL-9, IL-15 and IL-21. Binding of IL-7 to the alpha chain leads to dimerization of the alpha and gamma chains. JAK3 associated with the gamma chain tyrosine phosphorylates the alpha chain after dimerization. The importance of JAK3 in IL-7 signaling is supported by the similarity of the immune defects in JAK3 knockout mice and IL-7 knockout mice. The phosphorylated alpha chain serves as the site for recruiting other signaling molecules to the complex to be phosphorylated and activated, including STAT5, src kinases, PI3 kinase, Pyk2 and Bcl2 proteins. Some targets of IL-7 signaling contribute to cellular survival, including Bcl2 and Pyk2. Other targets contribute to cellular proliferation, including PI3 kinase, src family kinases (lck and fyn) and STAT5. The transcription factor STAT5 contributes to activation of multiple different downstream genes in B and T cells and may contribute to VDJ recombination through alteration of chromatin structure. The cell survival and cell proliferation signals induced by IL-7 combine to induce normal B and T cell development.
