These findings were extended by demonstrating reduced murine Tfh cells in vivo in the absence of one or more of these cytokines (Crotty, 2011; Tangye et al

These findings were extended by demonstrating reduced murine Tfh cells in vivo in the absence of one or more of these cytokines (Crotty, 2011; Tangye et al., 2013). effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation. Naive CD4+ T cells from humans and mice differentiate into distinct populations of effector cells with specialized functions. CD4+ T cell differentiation is mediated by the microenvironment in which the cells encounter and integrate various signals provided by APCs in the form of MHC class IICpeptide complexes, and co-stimulatory signals Btk inhibitor 1 provided by interacting surface receptors, cytokines, and associated signaling pathways and transcription factors. Thus, the generation of Th1 cells is driven by IL-12 and IFN-, which activate STAT4 and STAT1, respectively, to induce T-bet and promote IFN- production. Similarly, IL-4 activates STAT6 to induce GATA3 and cMaf to imprint a Th2 fate on naive CD4+ T cells. Th17 cells require TGF, IL-6, and Rabbit Polyclonal to STAT1 (phospho-Tyr701) IL-23, which, through STAT3 and RORt, induce the signature Th17 cytokines IL-17A, Btk inhibitor 1 IL-17F, and IL-22 (OShea and Paul, 2010; Zhu and Paul, 2010; Deenick et al., 2011; Zielinski et al., 2011; Vahedi et al., 2013). There also exists a population of effector CD4+ T cells that shares features of both Th1 and Th17 cells (termed Th1* or Th1/17 cells), insomuch that they produce IFN-, IL-17, and IL-22, express RORt and T-bet, and coexpress the chemokine receptors CXCR3 and CCR6, which typically define Th1 and Th17 cells, respectively (Annunziato et al., 2007; Morita et al., 2011; Becattini et al., 2015; Ma et al., 2015; Okada et al., 2015). Human Th1, Th17, and Th1/17 cells have important roles in host protection against different classes of pathogens. Indeed, patients with inborn errors of IFN- immunity are susceptible to infection with mycobacteria (Boisson-Dupuis et al., 2015; Kreins et al., 2015; Okada et al., 2015), whereas those with inborn errors of IL-17Cmediated immunity develop chronic mucocutaneous candidiasis (CMC; de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al., 2008; Liu et al., 2011; Puel et al., 2012; Okada et al., 2015). Another subset of effector CD4+ T cells, T follicular helper (Tfh) cells, mediates the differentiation of B cells into memory cells and plasma cells in response to T cellCdependent antigens (Crotty, 2011; Tangye et al., 2013). Tfh cells express CXCR5, the transcription factor Bcl-6, which is essential for Tfh generation, and a host of molecules involved in T cellCB cell interactions, including CD40L, inducible costimulator (ICOS), PD-1, SAP, and IL-21 (Crotty, 2011; Liu et al., 2013; Tangye et al., 2013). Many studies have addressed the requirements for Tfh formation. IL-6, IL-12, IL-21, and IL-27 can induce features of Tfh cells in human and murine naive CD4+ T cells in vitro (Crotty, 2011; Tangye et al., 2013). These findings were extended by demonstrating reduced murine Tfh cells in vivo in the absence of one or more of these cytokines (Crotty, 2011; Tangye et al., 2013). Studies in mice also identified receptor/ligand pairs (CD40/CD40L, ICOS/ICOS-L, SLAM family members, and CD28/B7), specific signaling pathways (SAP, PI3 kinase, STAT1, and STAT3), and transcription factors in addition to Bcl-6 (cMAF, IRF4, BATF, and Ascl2) that are involved in Tfh formation (Crotty, 2011; Tangye et al., 2013). More recently, an additional level of complexity has been added to Tfh biology, with several studies implicating roles for TGF and/or IL-23 in their formation in humans and mice (Schmitt et al., 2014; Marshall et al., 2015). Btk inhibitor 1 However, TGF also represses murine Tfh formation in vivo and in vitro (Suto et al., 2008; McCarron and Marie, 2014; Schmitt et al., 2014), indicating that the precise requirements for Tfh cell development remains to be established. Despite this, the importance of Tfh cells in humoral immunity is apparent from their dysregulated production and function in numerous human immunopathologies, such as autoimmunity and primary immunodeficiencies (PIDs; Tangye et al., 2013). Furthermore, frequencies of circulating Tfh (cTfh) cells correlates with the efficacy of humoral immune responses elicited after natural infection and vaccination (Pallikkuth et al., 2012; He et al., 2013; Locci et al., 2013; Herati et al., 2014). We and others have previously quantified CD4+ T cell subsets in individuals.