CTLA-4 Regulates Expansion and Differentiation of Th1 Cells Following Induction of Peripheral T Cell Tolerance

Abstract

Intravenous treatment with Ag (peptide)-coupled, ethylene carbodiimide-fixed syngeneic splenocytes (Ag-SP) is a powerful method to induce anergy in vitro and peripheral T cell tolerance in vivo. In this study, we examined the effects of Ag-SP administration on T cell activity ex vivo and in vivo using OVA-specific DO11.10 TCR transgenic T cells. Although treatment with OVA323–339-SP resulted in a strong inhibition of peptide-specific T cell recall responses in vitro, examination of the immediate effects of Ag-SP treatment on T cells in vivo demonstrated that tolerogen injection resulted in rapid T cell activation and proliferation. Although there was an increase in the number of OVA-specific DO11.10 T cells detected in the lymphoid organs, these previously tolerized T cells were strongly inhibited in mounting proliferative or inflammatory responses upon rechallenge in vivo with peptide in CFA. This unresponsiveness was reversible by treatment with anti-CTLA-4 mAb. These results are consistent with the hypothesis that Ag-SP injection induces a state of T cell anergy that is maintained by CTLA-4 engagement.

Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

“…Not surprisingly, costimulatory signals appear to play a dogmatic role in the regulation of Ag-SP tolerance induction. For example, low B7 expression on the donor-coupled cells is necessary for tolerance induction, while CTLA-4 is important for the maintenance phase of Ag-SP tolerance upon secondary encounter with Ag on stimulatory APCs expressing up-regulated levels of costimulatory molecules (14,15,24). Also, we have demonstrated that a chemical fixative, such as ECDI, is required during the coupling process (24,25).…”

“…Ag-SP is believed to render cells anergic due to a lack of costimulation (4). LPS-preactivated coupled cells with high B7 expression are incapable of inducing tolerance, suggesting that successful tolerance induction is dependent upon the lack of costimulatory signals coming from the APCs (14,15).…”

“…It was originally believed that the underlying mechanisms of Ag-SP-mediated functional tolerance were mediated by direct interactions between MHC II:peptide complexes and the TCR expressed by target CD4 ϩ T cells (14,15). However, alternative mechanisms may contribute to the induction of functional tolerance by Ag-SP as in addition to peptides, both whole protein (e.g., proteolipid protein (PLP) and myelin basic protein) and mouse spinal cord homogenate (MSCH) also efficiently induce tolerance in CD4 ϩ T cells and prevent EAE induced with defined encephalitogenic peptides when coupled to ECDI-fixed spleen cells (16 -18).…”

CTLA-4 Engagement Acts as a Brake on CD4+ T Cell Proliferation and Cytokine Production but Is Not Required for Tuning T Cell Reactivity in Adaptive Tolerance

“…Walker et al (62) also showed in a diabetes model that the magnitude of the initial T cell expansion in the spleen was not significantly affected by the absence of CTLA-4, but that the subsequent accumulation of T cells in the pancreatic LNs and the development of diabetes were greatly enhanced in the KO. Finally, Eagar et al (63) recently published that CTLA-4 blockade solely in the ear was sufficient to allow the onset of delayed-type hypersensitivity effector function in a fixed cell, Ag presentation, tolerance model. From all these experiments, we and others (19) would conclude that CTLA-4 only acts as a brake on CD4 ϩ TCR-induced responses, including proliferation, cytokine production, and homing.…”

Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model

“…3,4) and stimulates effector T-cell activation, expansion, function, and motility (5,6). blockade can also eliminate myeloid-derived suppressor cells (MDSC), which contributes to improving the survival of mice bearing ovarian tumors (7).…”