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.

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…The most intuitive explanation is that this simply reflects widespread T-cell activation. However, these CD4 1 CD25 1 T cells all stain brightly for FOXP3 suggesting an expansion of Treg, which attempt unsuccessfully to control the ensuing lymphoproliferation and autoimmunity [63]. Recently, using antibody blockade, CTLA-4 has been shown to regulate Treg numbers and homeostasis in intact mice [12].…”

Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+ Regulatory T Cells

“…However, its role in Treg development and homeostasis is less well defined. CTLA-4 does not appear to be obligatory for Treg generation because these cells are present in CTLA-4 KO mice (46) and are even found at increased numbers (47), suggesting it may be providing a negative feedback signal to maintain Treg homeostasis.…”

Biomarkers of Response to Immune Modulatory Therapies in Cancer

“…A consistent observation associated with anti-CTLA-4-mediated tumour rejection had been a positive shift in the intra-tumoural ratio of Teff to T reg . A number of studies had demonstrated that anti-CTLA-4-mediated expansion of both Teff and T reg in the blood and secondary lymphoid organs of mice [34][35][36]. It was therefore unclear how anti-CTLA-4 mAb act to preferentially expand Teff in the tumour whilst simultaneously expanding both populations in the periphery.…”