Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE).

Abstract

SummaryT cell receptor (TCR)-recognizing regulatory cells, induced after vaccination with self-reactive T cells or TC1K peptides, have been shown to prevent autoimmunity. We have asked whether this regulation is involved in the maintenance of peripheral tolerance to myelin basic protein (MBP) in an autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). Antigen-induced EAE in (SJL X B10.PL)F1 mice is transient in that most animals recover permanently from the disease. Most of the initial encephalitogenic T cells recognize MBP Acl-9 and predominantly use the TCR V[38.2 gene segment. In mice recovering from MBP-induced EAE, regulatory CD4 + T cells (Treg) specific for a single immunodominant TCR peptide B5 (76-101) from framework region 3 of the V[38.2 chain, become primed. We have earlier shown that cloned B5-reactive Treg can specifically downregulate responses to Acl-9 and also protect mice from EAE. These CD4 Treg clones predominantly use the TCtL V[314 or VI33 gene segments. Here we have directly tested whether deletion/blocking of the Treg from the peripheral repertoire affects the spontaneous recovery from EAE. Treatment of F1 mice with appropriate V[3-specific monoclonal antibodies resulted in an increase in the severity and duration of the disease: even relapses were seen in one-third to one-half of the Treg-deleted mice. Interestingly, chronic disease in treated mice appears to be due to the presence of Acl-9-specific T cells. Thus, once self-tolerance to MBP is broken by immunization with the antigen in strong adjuvant, TCR peptide-specific CD4 Treg cells participate in reestablishing peripheral tolerance. Thus, a failure to generate Treg may be implicated in chronic autoimmune conditions.

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

“…It is noteworthy that treatment of B10.PL mice with anti-TCR V␤14 mAb results in incomplete recovery and chronic disease, whereas mice treated with anti-V␤3 alone do not show a significant difference in the natural course of EAE (13). These data further suggest the critical role V␤14 ϩ CD4 ϩ Treg play in this model.…”

“…Furthermore, removal of the V␤14 ϩ T cell repertoire, by anti-V␤14 mAb treatment, results in exacerbation of EAE and is associated with poor recovery (13). Additionally we demonstrated that the adoptive transfer of clones of the V␤14 ϩ Treg in the presence, but not in the absence of CD8 ϩ T cells protected recipients from EAE (9,12).…”

“…Furthermore, the T cell repertoire reactive to this region cannot be tolerized by neonatal or i.v. tolerance-inducing protocols in either mice or rats (11,13,23). We and others have used different approaches to induce efficient expansion of TCR-peptide-reactive regulatory T cells in the hope of identifying the optimal protocol for the modulation of autoimmunity.…”

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

“…However, the adoptive transfer of MUC1-expanded CD4 ϩ CD25 Ϫ T cells from WT mice to MUC1-Tg mice to raise the level of MUC1-specific T cell help is a proof of principle that we believe can be applied to the clinic where patients would receive transfers of autologous Treg-depleted Th cells that are expanded to large numbers in vitro by stimulation with MUC1. Restoring the balance to the MUC1-specific immune response via the provision of a defined component, such as functional Th cells, may be a more feasible clinical approach to treating malignancies than global depletion of the patients' Tregs, which may be fraught with side effects such as autoimmunity (55)(56)(57)(58)(59)(60).…”

Role for MyD88, TLR2 and TLR9 but Not TLR1, TLR4 or TLR6 in Experimental Autoimmune Encephalomyelitis

“…EAE is suppressed by the activity of Tregs (83)(84)(85)(86), including central Tregs (54,87), via the action of IL-10 (84,86,88). Tregs are induced by CD4 + T cell activation in the presence of TGF-b (86), and their induction is inhibited by IL-6 via trans signaling of soluble IL-6R into T cells causing SMAD7 suppression of TGF-b signaling (89).…”