After an immune response the expanded population of antigen-specific CD4+ T

After an immune response the expanded population of antigen-specific CD4+ T cells contract to steady-state Rabbit Polyclonal to RGS10. levels. disease in a lymphopenic environment. Such Muscimol a targeted regulation of homeostasis within thin colonies of T cells with related TCR specificities for sub-threshold ligands can prevent the loss of unrelated TCRs during multiple responses helping preserve the valuable diversity of the repertoire. Introduction The number of T cells in the peripheral immune system is usually tightly regulated during. In the constant state homeostatic processes maintain a stable populace of helper T cells balancing thymic output with normal attrition (Freitas and Rocha 2000 Infections trigger a dramatic growth of otherwise rare antigen-specific T cells; but this is transient and the population density is usually restored soon after the pathogen is usually cleared. Furthermore a separate set of processes ensure that T cells capable of reacting to self-antigens are eliminated from the population by clonal deletion (Gardner Muscimol et al. 2008 These numerous elimination mechanisms must also be discriminating enough to ensure that a diverse set of T cell receptors (TCRs) are still retained in the peripheral repertoire in order to maintain defenses against as wide a variety of future infections as you possibly can. Since each T cell response yields a large frequency of expanded pathogen-specific T cells if the subsequent contraction was regulated by stochastic processes it could also lead to a large loss of unrelated “bystander” T cells and therefore a progressive loss of repertoire diversity over multiple infections. The cellular mechanisms that make sure such a precise homeostatic control especially for CD4+ T cells are not obvious. In the last two decades reductionist approaches to study this complex problem have focused on understanding the regulation of T cell survival – since the frequency of particular T cells and the diversity of the repertoire can be influenced by how each T cell survives. These studies have coalesced around a conceptual framework based on competition for limiting trophic resources keeping T cell subsets within certain populace limits (Freitas and Rocha 2000 Strong antigenic stimulation can allow the antigen-specific T cell figures to exceed these limits but the populace returns to competing for the limiting interactions after antigen clearance. The crucial trophic factors that anchor this process can be segregated into two groups – public and cognate. The former are sensed by receptors not related to the TCR and therefore do not respect the antigen specifities of the T cells competing for them. These include cytokines – such as Muscimol interleukin-2 (IL-2) IL-7 IL-15 thymic stromal lymphopoietin (TSLP) as well as nutrients co-stimulatory molecules etc. (Schluns and Lefrancois 2003 Surh and Sprent 2005 Takada and Jameson 2009 The cognate factors on the other hand require sensing via the TCR – the stimulatory antigen being the best example (Obar et al. 2008 Smith et al. 2000 Even within these models the relative contribution of either category to T cell survival especially in the context of CD4+ T cells is usually far from obvious. Early experiments suggested that TCR-major histocompatibility complex (MHC) interactions were quite critical for survival (Kirberg et al. 1997 Polic et al. 2001 Takeda et al. 1996 Tanchot et al. 1997 Subsequent experiments however controlling for factors such as cell proliferation and rejection concluded that MHC-II recognition was not necessary for CD4+ T cell survival – and therefore could not be the crucial determinant of their populace control (Dorfman et al. 2000 Grandjean et al. 2003 A second set of experiments critical to understand peripheral homeostasis is the behavior of CD4+ T cells in lymphopenic models. Under these conditions normally quiescent na?ve T cells can proliferate and differentiate even in the absence of their cognate antigen (Cho et al. 2000 Oehen and Brduscha-Riem 1999 In fact this behavior has severe clinical ramifications where Muscimol aggressive immunopathology results from the response of T cells in lymphopenic conditions generated during bone marrow transplants HIV infections etc. and even hampers standard tolerance induction (Brown et al. 2006 Schietinger et al. 2012 Singh et al. 2006 Wu et al. 2004 The common explanation for this.