CTLA-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity
ABSTRACT The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.
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- "Expression of OX40 on CD4 T cells during priming is highly CD28 (Walker et al., 1999) and IL2 dependent (Williams et al., 2007). Therefore an effective strategy for T regs is to compete for access to CD28-ligands during priming through expression of CTLA4, the CD28 competitor, required for T reg function (Wing et al., 2008; Schmidt et al., 2009), and now shown to actively deplete CD28- ligands from the antigen-presenting surface (Qureshi et al., 2011). "
ABSTRACT: PHYLOGENY SUGGESTS THAT THE EVOLUTION OF PLACENTATION IN MAMMALS WAS ACCOMPANIED BY SUBSTANTIAL CHANGES IN THE MAMMALIAN IMMUNE SYSTEM: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi) are members of an emerging family of innate lymphoid cells (ILCs) that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3 dependent regulatory T (T(regs)) cells that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the T(regs) that under normal circumstances are absolutely required to regulate CD4 effector cells.Frontiers in Immunology 02/2012; 3:24. DOI:10.3389/fimmu.2012.00024
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ABSTRACT: CTLA-4 has potent regulatory effects on the threshold of T-cell signalling and, in the process, guards against the development of hyper-proliferation and autoimmunity. Despite this, the role of CTLA-4 on specific T-cell subsets has been unclear. Such studies could shed light on both the function of CTLA-4, and on the contribution of the subsets to the disease phenotype of the Ctla4(-/-) mouse. Recently, a role for this co-receptor in the function of Treg has been outlined and, in this issue of the European Journal of Immunology, the selective targeting of the T-box transcription factor Eomes by CTLA-4 in the regulation of CD8(+) cytolytic T-cell (CTL) effector function is shown. Together, these papers shed light on the role of CTLA-4 in different T-cell subsets.European Journal of Immunology 03/2009; 39(3):687-90. DOI:10.1002/eji.200939261 · 4.52 Impact Factor
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ABSTRACT: In the past 15 years, regulatory T cell (Treg) suppression has graduated from a phenomenon that 'dare not speak its name' to a field at the centre of a global research effort. It is now accepted that Tregs can target numerous cell populations to elicit potent immunosuppression. Intriguingly, emerging data suggest that certain signals can confer resistance to Treg suppression. Moreover, such resistance may be relevant to the pathogenesis of autoimmune diseases. In this article I review various pathways linked to resistance to Treg suppression. These include Toll-like receptor (TLR) signals, cytokines [in particular those that use the common gamma chain, such as interleukin (IL)-7 and IL-21] and the triggering of tumour necrosis factor (TNF) receptor family members (such as glucocorticoid induced tumor necrosis factor receptor (GITR), OX40 and 4-1BB). I also propose a model of 'tuned suppression' in which inflammatory stimuli and TLR ligation actively promote Treg function, such that as soon as effector cells re-acquire sensitivity to suppression the immune response can be efficiently curtailed.Immunology 05/2009; 126(4):466-74. DOI:10.1111/j.1365-2567.2009.03053.x · 3.74 Impact Factor