Infectious Tolerance

Abstract

Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, freshly isolated CD4+ T helper (Th) cells. This infectious suppressive activity, transferred from CD25+ Treg cells via cell contact, is cell contact–independent and partially mediated by soluble transforming growth factor (TGF)-β. The induction of suppressive properties in conventional CD4+ Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-β in CD25+ Treg cell–induced immunosuppression.

A dual altered peptide ligand down-regulates myasthenogenic T cell responses by up-regulating CD25- and CTLA-4-expressing CD4+T cells

“…Recently, it was proposed by Jonuleit et al (28) that the CD4 ϩ CD25 ϩ T cells may not represent the regulatory T cell population per se, but rather a population that is required for the differentiation and expansion of bona fide regulatory T cells that release inhibitory mediators such as biologically active TGF-␤. This secondary systemic suppressive effect mediated by induced suppressor cells is cell contact independent (28). We show here that CD4 ϩ CD25 ϩ cell depletion resulted in a decrease in TGF-␤ secretion, accompanied by an elevation in IFN-␥ secretion.…”

Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

“…Similarly, increased CD4 + CD25 + Foxp3 + T cell numbers were correlated with viral propagation during simian immunodeficiency virus (SIV)‐infection 12, 13. Previously, TGF‐β from CD4 + CD25 + Foxp3 + T cells represented a mechanism of infectious tolerance 14, was produced in abundance by CD4 + CD25 + Foxp3 + T cells, and was positively correlated with hepatitis virus levels in infected patients 15, 16, 17. Thus, CD4 + CD25 + Foxp3 + T cell‐mediated immune suppression may facilitate persistence of viral infections.…”

IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+T lymphocytes

“…ϩ CD25 ϩ T cells may also convert CD4 ϩ helper T cells into regulatory cells expressing IL-10 and͞or TGF-␤ in culture systems (6)(7)(8). In vivo, IL-10 and͞or TGF-␤ seem critical for regulatory T cell activity (9,10).…”