Deletion of CTLA-4 on Regulatory T Cells During Adulthood Leads to Resistance to Autoimmunity

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2015 Sep 16

PMID 26371185

Citations 117

Authors

Alison M Paterson

Scott B Lovitch

Peter T Sage

Vikram R Juneja

Youjin Lee

Justin D Trombley

Carolina V Arancibia-Carcamo

Raymond A Sobel

Alexander Y Rudensky

Vijay K Kuchroo

Gordon J Freeman

Arlene H Sharpe

Affiliations

Soon will be listed here.

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell responses. Germline Ctla4 deficiency is lethal, making investigation of the function of CTLA-4 on mature T cells challenging. To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated Ctla4 in adult mice. We show that, in contrast to germline knockout mice, deletion of Ctla4 during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and does not lead to increased resistance to MC38 tumors. Deletion of Ctla4 during adulthood was accompanied by activation and expansion of both conventional CD4(+)Foxp3(-) (T conv) and regulatory Foxp3(+) (T reg cells) T cell subsets; however, deletion of CTLA-4 on T reg cells was necessary and sufficient for protection from EAE. CTLA-4 deleted T reg cells remained functionally suppressive. Deletion of Ctla4 on T reg cells alone or on all adult T cells led to major changes in the Ctla4 sufficient T conv cell compartment, including up-regulation of immunoinhibitory molecules IL-10, LAG-3 and PD-1, thereby providing a compensatory immunosuppressive mechanism. Collectively, our findings point to a profound role for CTLA-4 on T reg cells in limiting their peripheral expansion and activation, thereby regulating the phenotype and function of T conv cells.

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