Th17 cells did not survive on low dose peptide. actions of cytokine and peptide level, with Th1 cells exhibiting the highest avidity, followed by Th17 and Th2 cells. Together, these data show that this interplay of antigen and cytokine signals shape both the differentiation fate and avidity setpoint of CD4+ T cells. Introduction Following LY-2584702 activation, na?ve CD4+ T cells will undergo a program of differentiation that results in the ability to produce a defined set of cytokines . The nature of cytokines produced by the differentiated CD4+ T cells identifies them as one of a number of distinct subsets that include, but are not limited to Th1, Th2 and Th17. The fate choice of these cells has profound implications for their function in vivo. Th1 cells are defined by the production of high levels of IFN and play a critical role in the clearance of intracellular pathogens. While this has been thought to occur primarily through their support of CD8+ T cell and B cell activation/function, it is increasingly clear that Th1 Bmp7 cells can play a direct role in pathogen clearance through a variety of mechanisms including cytolysis, IFN production, and enhancement LY-2584702 of innate inflammatory cytokines and chemokines C. Th2 cells produce a number of cytokines including IL-4 and IL-5. These cells support B cell production of high affinity antibody which is usually efficient in the clearance of extracellular parasites. The more recently described Th17 subset is usually a key mediator of the inflammatory response. Among their functional attributes is the recruitment of neutrophils that are necessary for the clearance of LY-2584702 extracellular bacterial and LY-2584702 fungal infections . CD4+ T cell differentiation is usually regulated by cytokine signals present in the environment during their activation and growth . IL-12 together with IFN induce Th1 cell development, while IL-4 drives differentiation into Th2 effectors. Th17 cells are generated as a result of signals from low dose TGF in combination with inflammatory cytokines such as IL-6 or IL-21. Cytokine mediated differentiation is usually controlled by a defined signal transducer and activator of transcription (STAT) and a grasp regulatory LY-2584702 transcription factor (for review see ). For Th1 these are STAT4 and T-bet, for Th2 STAT-5 and GATA-3, and for Th17 STAT-3 and RORt (for review see ). In addition to cytokines, antigen dose is recognized as a regulator of CD4+ T cell subset differentiation C. The vast majority of the studies in this area have focused on Th1 vs. Th2 differentiation. While the conclusions from the studies of antigen dose driven differentiation may appear to disagree in some cases, direct comparison is usually often complicated by the limited dose ranges chosen for evaluation , , C. However, in total, the data generated have led to the proposal of a biphasic model for antigen mediated differentiation where, in the absence of added differentiating cytokines, limiting or high doses of peptide promote Th2 differentiation whereas intermediate doses skew towards Th1 development . The regulatory effect of peptide/MHC (pMHC) level has been most highly studied in the context of CD8+ T cell differentiation, where it has been identified as an important regulator of T cell avidity. Functional avidity is usually defined by the amount of antigenic peptide required to elicit T cell activation or effector function, with high avidity cells exhibiting greatly increased sensitivity to pMHC , . This property is a critical attribute of effector cells. Multiple studies have shown that higher functional avidity is associated with superior in vivo efficacy for pathogen clearance , C. Our previous studies of CD8+ T cells exhibited that avidity is usually a plastic house.