We identify these cells as Treg and Th, respectively
We identify these cells as Treg and Th, respectively. Open in a separate window Figure 1 Computational model of T cell differentiation: (A) Signaling network connections. abundance and Akt/mTOR activation that correlated with these T cell fates. Further analysis of corresponding simulation trajectories implicated a negative feedback loop involving Foxp3, PTEN, and Akt/mTOR. Taken together, these results suggest that there is a crucial period Pranoprofen following TCR stimulation during which heterogeneity in the differentiating populace leads to increased plasticity of cell fate. Introduction CD4+ T cells can be grouped into two main sub-types: those which exert an activating effect on the immune response Pranoprofen (helper T cells, Th), and those which suppress immune responses (regulatory T cells, Treg). Treg cells play an important role in suppressing T cell mediated immunity, limiting damage caused by the immune response and preventing autoimmune diseases (1). However, Treg cells may play a detrimental role in cancer by acting as an effector of immune suppression by tumors. In several recent studies of human Treg cells in patients with cancer, the number of Treg cells within tumors and their suppressive activity were found to be elevated and to predict poor survival (2). Understanding the factors that control the induction of Treg cells has the potential to advance therapies involving either elimination of antigen-specific Treg cells in the context of cancer (3), or enhancement of Treg-mediated suppression in the context of autoimmune responses (4). Treg cells are characterized by the transcription factor forkhead box P3 (Foxp3), a specific pattern of cytokine production, and immunosuppressive function (5C7). Treg cells suppress other effector T cells through several mechanisms (8), including deletion of effector cells via granzyme B (9), secretion of immunosuppressive cytokines such as transforming growth factor (TGF-), interleukin (IL-)10 and IL-35 (10), metabolic disruption through the production of adenosine (11) or competition for IL-2 (12, 13) and finally, inhibition of dendritic cell maturation(8, 14).Two main groups of Treg cells are currently known: natural and adaptive (induced) Treg cells. Natural regulatory T (nTreg) cells become committed to a regulatory fate while still in the thymus (14), whereas induced Treg (iTreg) cells, arise from na?ve T cells in the periphery under stimulation by specific factors including IL-10 (15), TGF- (16), low antigen (Ag) dose (17, 18), and certain dendritic cell (DC) subsets (19C21). iTreg and Th both develop in the periphery from common, na?ve, uncommitted T cell precursors, which differentiate upon encountering cognate peptide:major histocompatibility complex (pMHC) on the surface of antigen-presenting cells (APC). Previous studies have indicated that both Ag dose and the duration of Ag stimulation strongly influence the choice between regulatory and helper cells in the T cell response specific for a particular Ag, such that high dose favors Th and low dose favors Treg (17, 18, 22). Understanding the molecular determinants of this process has major implications for the development of targeted immunomodulation therapies (23). For example, it is important in a cancer vaccination strategy to deliver a high enough dose to induce tumor-specific Th1 cells. A more delicate balance must be achieved in the context of autoimmunity, because many patients have increased Pranoprofen numbers of auto-reactive T cells, which any therapy must avoid activating. Thus, a strategy designed to induce Ag-specific Treg must CD117 deliver a dose that will favor the induction of self-Ag-specific Treg without activating or inducing autoreactive Th1/Th17 cells. Few vaccination strategies in cancer or autoimmunity consider the dose of the Ag and this may be one reason for the limited success of these efforts to date (24, 25). Treg differentiation is usually influenced by multiple signaling pathways including those stimulated by engagement of T cell receptor (TCR), the co-stimulatory molecule CD28, IL-2 receptor (IL-2R) and TGF- receptor (TGF-R). We recently reported that this culture of CD4+ T cells with DC presenting low dose Ag resulted in both the growth of preexisting nTreg and the conversion of na?ve T cells into iTreg (18), and the induction of Treg was inversely correlated with Pranoprofen the strength of the TCR signal as measured by phosphorylation of the S6 ribosomal protein (pS6). pS6 is usually downstream of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway and several other studies have found that activation.