The importance of this protein is clearly demonstrated by the observation that mice deficient in CTLA-4 die within 2C3?weeks from major organ lymphocytic infiltration and destruction, resulting from uncontrolled lymphocyte proliferation (13). we discuss the origin and generation, homeostasis, and functions of Tregs, particularly their roles and effects Rabbit Polyclonal to Histone H3 in HIV infection. We also present various Treg manipulation strategies, including Treg depletion techniques and interventions that alter Treg function, which may be used in different cure strategies, to simultaneously boost HIV-specific immune responses and induce reactivation of the latent virus. gene that codes for FoxP3 were shown to cause the X-linked recessive disease, scurfy, in mice. Scurfy presents as lymphoproliferation leading to fatal autoimmunity, and mimics X-linked autoimmunity-allergic dysregulation syndrome in humans (7). Scurfy mice administered with stable Tregs, defined by FoxP3 expression and full suppressive functionality, did not develop any signs of the disease (8). FoxP3 expression can also be transiently induced following stimulation of nonsuppressive CD25neg CD4+ T cells, which indicates that expression of FoxP3 alone is not responsible for the regulatory activity of T cells (52). Thymic Tregs are defined by the expression of CD25 and FoxP3 on CD4+ T cells. It has been shown that CD25hi CD4+ Treg cells develop from self-reactive thymic cells that express a T cell receptor (TCR) with high affinity for self-antigens. Differentiation occurs as an alternative mechanism to apoptosis, such that self-antigen reactivity can induce an inhibitory response instead of an autoimmune response (53). Upon TCR interaction with these peptide-major histocompatibility complex (MHC) complexes, FoxP3 is induced in the immature thymocytes (54). However, FoxP3 expression is not sufficient to create a stable Treg. Demethylation of the FoxP3 locus in the Treg-specific demethylated region (TSDR) is required to generate stable tTregs (55). In addition, CpG hypomethylation of certain JT010 loci called Treg cell representative regions is imprinted in Tregs, JT010 also contributing to their stability (56). Interactions between B7 molecules (CD80 and CD86), expressed on the antigen-presenting cells (APCs), and CD28, on thymocytes, are co-stimulatory and are critical to the thymic development of Tregs, as evidenced by the severe decrease in Treg numbers in mice either deficient in CD28 or treated with a blocking anti-B7 antibody (15, 57, 58). Interleukin-2 (IL-2), the central cytokine involved in Treg biology, is also essential for tTreg maturation (59). In addition to tTregs, it has become clear that expression of FoxP3 can occur in non-Treg CD4+ T cells, either or (61); however, it is now recognized that these induction of FoxP3+ cells (67). Another pathway involved in pTreg induction is antigen presentation by immature DCs. Notably, it has been shown that delivering peptides in subimmunogenic forms for a prolonged period of time can result in the induction of CD4+CD25+ Tregs from na?ve T cells in peripheral lymphoid organs, even in the absence of a functional thymus (68). Treg Homeostasis It was thought that IL-2 is the most important Treg regulator, being required for both Treg maintenance and function (69, 70). More recently, it was shown that Tregs form two distinct populations, the CD44lo CD62Lhi central Tregs, which actively recirculate through lymphoid organs and are sustained by paracrine IL-2, and the CD44hi CD62Llo CCR7lo effector Tregs, which are not JT010 found in the lymphoid tissue, do not require IL-2, and are instead maintained by inducible costimulator (ICOS) (71). deletion and subsequent Treg cotransfer experiments in mice, the inhibition of Th1 differentiation and colitis was shown to be dependent upon TGF-1 production by Tregs (46). Additional studies with TGF-1 blockades have further supported its role as a mediator of Treg suppressive function (47, 48). TGF-1 primarily inhibits type 1 T-helper cell (Th1) responses by blocking differentiation through the inhibition of the master regulator T-bet. However, TGF-1 is also able to directly suppress the effector functions of CD8+ T cells through inhibiting cytokine and effector molecule secretion (49). Beyond direct suppression, TGF- signaling is important for inducing Treg trafficking to the gut, where they can then modulate gut JT010 Th17?cells and gut inflammation (50). T regulatory cells also produce IL-10, which has been shown to be important in controlling inflammation, as disruption of IL-10 production caused colitis in mice. However,.