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.
"30 In contrast, CTLA-4 does not affect Foxp3+ frequencies in thymocytes from mice with a normal TCR repertoire. CTLA-4 could still have an effect on the repertoire of Foxp3+ Treg cells, as CTLA-4 deficiency has been reported to reduce Foxp3 induction in the thymus of one TCR transgenic mouse line, but not all TCR transgenic mouse lines are affected by the lack of CTLA-4.31, 32 "
[Show abstract][Hide abstract] ABSTRACT: Thymic induction of CD4(+)Foxp3(+) regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4(+) T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4(+) T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Foxp3 and maintenance of Foxp3 populations in the spleen and mesenteric lymph nodes, but their accumulation in the colon, where Treg cells specific for commensal bacteria accumulate, is impaired. In a T cell-transfer model of colitis, the two known CTLA-4 ligands, B7-1 and B7-2, had largely redundant roles in inducing inflammation and promoting Treg cell function. However, B7-2 proved more efficient than B7-1 in inducing Foxp3 in vitro and in vivo. Our data reveal an unappreciated role for CTLA-4 in establishing the Foxp3(+) compartment in the intestine.Mucosal Immunology advance online publication 22 August 2012; doi:10.1038/mi.2012.75.
"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). "
[Show abstract][Hide abstract] 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
"Loss of function of CTLA-4 results in massive lymphoproliferation in CTLA-4–deficient mice, which die 3–4 weeks after birth. In parallel, blocking of endogenous CTLA-4 by injection of anti–CTLA-4 mAbs results in rapid β-cell destruction, indicating that the autoimmune response can be augmented in the absence of coinhibitory molecules (20,21). Consistent with this notion, systemic administration of CTLA-4.Ig prevents autoimmune diabetes by competing with CD28 for binding to CD80/CD86, confirming that coinhibitory molecules can turn off autoreactive T-cell proliferation through blocking the action of positive cosignaling molecules (15). "
[Show abstract][Hide abstract] ABSTRACT: Autoimmune diabetes is a T cell-mediated disease in which insulin-producing β-cells are destroyed. Autoreactive T cells play a central role in mediating β-cell destruction. B7-H4 is a negative cosignaling molecule that downregulates T-cell responses. In this study, we aim to determine the role of B7-H4 on regulation of β-cell-specific autoimmune responses.
Prediabetic (aged 3 weeks) female NOD mice (group 1, n = 21) were treated with intraperitoneal injections of B7-H4.Ig at 7.5 mg/kg, with the same amount of mouse IgG (group 2, n = 24), or with no protein injections (group 3, n = 24), every 3 days for 12 weeks.
B7-H4.Ig reduced the incidence of autoimmune diabetes, compared with the control groups (diabetic mice 28.6% of group 1, 66.7% of group 2 [P = 0.0081], and 70.8% of group 3 [group 1 vs. 3, P = 0.0035]). Histological analysis revealed that B7-H4 treatment did not block islet infiltration but rather suppressed further infiltrates after 9 weeks of treatment (group 1 vs. 2, P = 0.0003). B7-H4 treatment also reduced T-cell proliferation in response to GAD65 stimulation ex vivo. The reduction of diabetes is not due to inhibition of activated T cells in the periphery but rather to a transient increase of Foxp3(+) CD4(+) T-cell population at one week posttreatment (12.88 ± 1.29 vs. 11.58 ± 1.46%; n = 8; P = 0.03).
Our data demonstrate the protective role of B7-H4 in the development of autoimmune diabetes, suggesting a potential means of preventing type 1 diabetes by targeting the B7-H4 pathway.
Eva Rosenkranz, Ralf-Dieter Hilgers, Peter Uciechowski, Arnd Petersen, Birgit Plümäkers, Lothar Rink,
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