Interleukin-2 Signaling and Inherited Immunodeficiency

Recent work has suggested that a number of proteins may be involved in the control of STAT-mediated transcriptional activation (fig. 1fig. 1). A 45-kD Myc-binding protein, Nmi, can associate with STAT5 and may play a role in modulating many cytokine and interferon responses, including IL-2 (Zhu et al. 1999xFunctional association of Nmi with Stat5 and Stat1 in IL-2- and IFNγ-mediated signaling. Zhu, MH, John, S, Berg, M, and Leonard, WJ. Cell. 1999; 96: 121–130Abstract | Full Text | Full Text PDF | PubMed | Scopus (200)See all References1999). Another family of proteins, PIAS (protein inhibitor of activated STAT), interacts with and specifically inhibits the DNA binding activity of STAT molecules. PIAS3 associates with STAT3 in response to IL-6, ciliary neurotrophic factor, and oncostatin M, and the interactions appear to be specific, since PIAS1 is not coprecipitated with STAT2 or STAT3 and since PIAS3 does not associate with STAT1 (Chung et al. 1997xSpecific inhibition of STAT3 signal transduction by PIAS3. Chung, CD, Liao, J, Liu, B, Rao, X, Jay, P, Berta, P, and Shuai, K. Science. 1997; 278: 1803–1805Crossref | PubMed | Scopus (631)See all References1997). The exact mechanism by which these proteins affect STATs requires further study.Recently, the protein tyrosine phosphatase SHP-1 has been reported to be recruited to the IL-2R in a ligand-dependent manner. SHP-1 can dephosphorylate both Jak1 and IL-2Rβ, and its expression in IL-2–responsive cells markedly reduces the steady-state phosphorylation levels of both Jak1 and Jak3. Moreover, constitutive activation of the IL-2 signaling pathway has been observed in human T-cell leukemia virus-1–transformed T cells and in Sezary syndrome (O'Shea 1997xJaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet?. O'Shea, JJ. Immunity. 1997; 7: 1–11Abstract | Full Text | Full Text PDF | PubMed | Scopus (323)See all References1997), with an associated loss of SHP-1 expression (Migone et al. 1998xRecruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor: loss of SHP-1 expression in human T-lymphotropic virus type 1-transformed T cells. Migone, TS, Cacalano, NA, Taylor, N, Yi, T, Waldmann, TA, and Johnston, JA. Proc Natl Acad Sci USA. 1998; 95: 3845–3850Crossref | PubMed | Scopus (98)See all References1998). This is interesting, because peripheral T cells from SHP-1–deficient, “moth-eaten” mice exhibit enhanced proliferation to mitogens and IL-2, which further suggests that SHP-1 has an important role in the control of proliferation.Another family of cytokine-induced inhibitory proteins, reported by several groups, includes variously named suppressors of cytokine signaling (SOCS), cytokine-induced SH2 proteins (CIS), or STAT-induced STAT inhibitors (SSI). SOCS-1 was cloned because of its ability to inhibit IL-6–mediated differentiation of a myeloid cell line, M1 (Endo et al. 1997xA new protein containing an SH2 domain that inhibits JAK kinases. Endo, TA, Masuhara, M, Yokouchi, M, Suzuki, R, Sakamoto, H, Mitsui, K, Matsumoto, A et al. Nature. 1997; 387: 921–924Crossref | PubMed | Scopus (1063)See all References1997; Starr et al. 1997xA family of cytokine-inducible inhibitors of signalling. Starr, R, Willson, TA, Viney, EM, Murray, LJ, Rayner, JR, Jenkins, BJ, Gonda, TJ et al. Nature. 1997; 387: 917–921Crossref | PubMed | Scopus (1480)See all References1997). The mechanism of cytokine inhibition by SOCS family members is an area of intense investigation. CIS can inhibit IL-3 and erythropoietin responses by competing for a receptor phosphotyrosine residue that serves as a STAT docking site, which suggests that CIS is a direct competitive inhibitor of STAT activation. On the other hand, SOCS-1 and SOCS-3 inhibit cytokine responses by binding to that catalytic domain and inhibiting Jak activity. SOCS-3 expression is rapidly induced in lymphocytes in response to IL-2 (as are SOCS-1 and CIS) and has been shown to specifically inhibit IL-2–mediated STAT activation. Because these proteins may be important in the progression of T-cell–mediated inflammatory disease, they will no doubt be subject to intense investigation.Despite these recent advances, our understanding of cytokine signaling remains sketchy in several respects. In particular, the pathways that control T-cell expansion and apoptosis are not understood in detail. The identification of novel families of proteins—such as SOCS, Nmi, and PIAS—that are induced by IL-2, points to an unexpected degree of complexity in downstream regulation of cytokine responses. The study of these proteins may shed some light on cross-talk that integrates the various signaling mechanisms within the cytoplasm, and it should help to pinpoint biochemical imbalances that manifest as autoimmune disorders or chronic inflammatory diseases.Finally, the current understanding of cytokine signaling has identified targets for therapeutic intervention. For example, inhibitors of the Jak/STAT pathway may be valuable in the treatment of allergic disease, in transplantation therapy, and in the treatment of lymphomas in which constitutive Jak/STAT activity has been observed. Also, the identification of the genetic defects in several forms of SCID raises the possibility of therapeutic intervention with a gene-therapy approach. Studies in mice have proved that retroviral-mediated transduction of the wild-type genes for γc and Jak3 rescues lymphocyte development and immune function in mice that are deficient for γc- and Jak3. Perhaps this approach will be feasible for human immunodeficiencies.