For example, mutations in the c receptor subunit or JAK3 result in severe combined immunodeficiency (SCID) diseases (16C19). a large body of literature has identified IL-2 as a pivotal cytokine responsible for the formation and function of lymphocyte populations, including CD4+ T helper cells. IL-2 exhibits a broad range of functions across T helper cell populations and is an essential regulator of numerous signaling pathways, including those underlying cell survival, proliferation, differentiation, and effector functions. Thus, predictably, dysregulation of IL-2 signaling has been identified as a key factor in the genesis of autoimmune disorders and MF1 immunodeficiency. Here, Vacquinol-1 we discuss basic aspects of the IL-2 signaling pathway and its pleiotropic effects on the differentiation of effector and regulatory CD4+ T cell populations. Structure, binding affinity, and regulation of the IL-2 receptor IL-2 signals through a heterotrimeric receptor composed of IL-2R, IL-2R, and the gamma common (c) chain subunits (2C8). Expression of individual subunits varies across immune cell populations, and expression levels are dependent upon both immune cell activation state and cytokine signals. In CD4+ T cells, while the c chain is expressed constitutively, IL-2R and IL-2R expression are upregulated following T cell receptor (TCR) stimulation and further induced by STAT5 activity downstream of IL-2 signaling (2, 9C12). In the presence of environmental IL-2, assembly of the trimeric form of IL-2R occurs sequentially, beginning with IL-2/IL-2R binding, followed by association with IL-2R and subsequent c chain recruitment. Formation of this heterotrimeric receptor results in high-affinity IL-2 signaling (12, 13). While the trimeric receptor combination predominates, weaker signals may be relayed through IL-2R/c, though downstream mechanisms are altered due to diminished IL-2-receptor binding affinity (14, 15). Highlighting the importance of effective IL-2 signaling in Vacquinol-1 immune function, mutations in IL-2R and downstream signaling molecules have been implicated in the generation of disrupted immune cell responses in humans. For example, mutations in the c receptor subunit or JAK3 result in severe combined immunodeficiency (SCID) diseases (16C19). Conversely, patients with IL-2R or IL-2R mutations develop autoimmune disease, due to disrupted immune tolerance, while paradoxically also exhibiting immunodeficiency (2, 20C23). Given its role in such disease states, the IL-2 signaling pathway is an attractive target for a number of immunotherapies, which focus on modulation of IL-2 responses to target individual Vacquinol-1 T cell populations for the treatment of not only autoimmune disease, but also graft versus host disease (GVHD) and cancer. Different strategies to manipulate IL-2 signaling for therapeutic benefit will be briefly discussed below and have also been extensively reviewed elsewhere (2, 12, 24). IL-2 signaling pathways IL-2 signaling is propagated through a number of signaling cascades, including the Janus Kinase (JAK)/STAT pathway (12, 13). Upon high-affinity IL-2 signaling, JAK1 and JAK3 associate with IL-2R and c, respectively, resulting in cross-phosphorylation and JAK activation (18, 25C30). Next, JAK1 and JAK3 phosphorylate specific tyrosine resides on IL-2R, allowing for recruitment of members of the Signal Transducer and Activator of Transcription (STAT) family via their conserved SH2 domain (27, 31) (Fig. 1). While IL-2 has been shown to activate several STAT family members, including STAT1, Vacquinol-1 STAT3, and STAT5, STAT5 is the predominant IL-2 signaling molecule (32, 33). Upon recruitment, two STAT5 isoforms are activated via JAK-mediated phosphorylation of the tyrosine 694 (STAT5A) and 699 (STAT5B) residues (34, 35) (Fig. 1). This results in STAT5 dimerization, nuclear translocation, and downstream transcriptional activities via direct DNA binding and co-factor recruitment (30). It is important to note that in addition to IL-2, signals from other cytokines, including IL-7, IL-9, and IL-15, are also propagated through STAT5. While this review focuses on the role of STAT5 downstream of signals from IL-2, these other STAT5-dependent pathways have been expertly discussed elsewhere.