Signaling via TLR2 and TLR4 directly down-regulates T cell effector functions: The regulatory face of danger signals

Abstract

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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 TLR-2-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 TLR-4 activation; nevertheless, TLR-2 engagement by HSP60 on T cells can lead to resolution of inflammation by up-regulating the suppressive function of regulatory T cells and shifting the resulting cytokine secretion balance towards a Th2 phenotype. Moreover, T-cell TLR-4 engagement by LPS leads to up-regulation of SOCS3 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.

Keywords

• Inflammation
• HSP60;
• TLR2;
• TLR4;
• direct signaling;
• T cell inhibition;