Signaling via TLR2 and TLR4 Directly Down-Regulates T Cell Effector Functions: The Regulatory Face of Danger Signals

Alexandra Zanin-Zhorov,Irun R Cohen

doi:10.3389/fimmu.2013.00211

Abstract

Toll-like receptors (TLRs) are widely expressed and play an essential role in the activation of innate immune cells. However, certain TLRs are also expressed on T cells, and TLR ligands can directly modulate T cell functions. Here, we discuss findings indicating that T cells directly respond to Heat Shock Protein (HSP) 60, a self molecule, or to the HSP60-derived peptide, p277, via a TLR2-dependent mechanism. HSP60 has been considered to be a “danger signal” for the immune system because of its ability to induce pro-inflammatory phenotypes in innate immune cells – in this case via TLR4 activation; nevertheless, TLR2 engagement by HSP60 on T cells can lead to resolution of inflammation by up-regulating the suppression function of regulatory T cells and shifting the resulting cytokine secretion balance toward a Th2 phenotype. Moreover, T cell TLR4 engagement by LPS leads to up-regulation of suppressor of cytokine signaling 3 expression and consequently down-regulates T cell chemotaxis. Thus, TLR2 and TLR4 activation can contribute to both induction and termination of effector immune responses by controlling the activities of both innate and adaptive immune cells.

Highlights

TOLL-LIKE RECEPTORS FUNCTION IN INNATE AND ADAPTIVE IMMUNE CELLS A key issue in immunology is to understand how the immune system is able to discriminate between self and non-self, inhibiting autoimmune responses, but allowing effective immune responses against microbial antigens [1, 2]
More recent Toll-like receptors (TLRs) expression profiling studies have revealed that certain TLRs are expressed in innate immune cells and in various adaptive immune cells, such as B cells [10, 11], CD4+ and CD8+ [12, 13], γδ T cells [14], and the CD4+CD25+ regulatory T cell population [15,16,17]; TLR ligands can directly modulate the function of these adaptive immune cells
A large multi-center phase III trial of p277 (DiaPep277) has confirmed the finding of the published phase II study. These results suggest that treatment with HSP60 or its p277 peptide can lead to the induction of HSP60specific regulators, including anti-ergotypic regulators [40] that can control the collective of pathogenic re-activities involved in the progression of autoimmune diabetes

Summary

Introduction

TOLL-LIKE RECEPTORS FUNCTION IN INNATE AND ADAPTIVE IMMUNE CELLS A key issue in immunology is to understand how the immune system is able to discriminate between self and non-self, inhibiting autoimmune responses, but allowing effective immune responses against microbial antigens [1, 2]. TLR2 SIGNALING MEDIATES THE INNATE EFFECTS OF HSP60 ON T CELLS Heat shock proteins (HSP) are highly conserved proteins induced in response to cellular stress, such as heat shock or nutrient deprivation [24, 25], and function as an endogenous danger signal of the immune system.

Results

Conclusion