Coexpression of TLR2 or TLR4 with HLA-DR Potentiates the Superantigenic Activities ofMycoplasma arthritidis–Derived Mitogen

Abstract

Mycoplasma arthritidis–derived mitogen (MAM) is a member of the superantigen family that structurally differs from other members while still capable of initiating cognate APC/T cell interaction. In addition to the critical role of MHC class II molecules, it has been suggested that TLR2 and TLR4 may cooperate with MHC class II during MAM-induced responses. In this study, we investigated the direct involvement of TLR2 and TLR4 in MAM binding and presentation to T cells. Our results showed that MAM fails to bind to TLR2- and TLR4-transfected cells. However, coexpression of TLR2 or TLR4 with HLA-DR significantly increases MAM binding and the subsequent T cell activation compared with cells expressing HLA-DR alone. The upregulated MAM binding and activity in HLA-DR/TLR–transfected cells is abrogated by an anti–HLA-DR Ab. Interestingly, we also found that MAM complexed with soluble HLA-DR is capable of binding to both TLR2 and TLR4. The enhancing effect of TLR2 or TLR4 on MAM-induced T cell proliferation was not due to TLR ligand contamination in the MAM preparation. Taken together, these results strongly suggest that binding of MAM to HLA-DR leads to a conformational change in MAM structure allowing its interaction with TLR2 and TLR4 and a better recognition by T cells.

Virulence Effectors of Pathogenic Mycoplasmas

“…In addition, Mu et al (2005Mu et al ( , 2011 used TLR blocking antibodies and TLR2 or TLR4 deficient mice to show that MAM interacts directly with certain TLRs, possibly by cross-linking them with MHC class II molecules. The interaction is potentiated by co-expression of the MHC class II cell-surface receptor HLA-DR (Shio et al, 2014). The TLR2 + /TLR4 + mouse TH cytokine response to MAM is anti-inflammatory, dominated by IL-4, IL-6 and IL-10, but in TLR4 -mice a proinflammatory IFN, TNF and IL-12 response dominates.…”

Bacterial superantigens and superantigen-like toxins

“…In mice treated with anti-B7-1 antibody, both MAM and TLR4 were required for a systemic and local joint stimulation of the Th17/IL-17 cascade illustrating how microbial agonists can promote chronic inflammatory and autoimmune disease by redirecting signaling pathways [218]. Interestingly, Shio et al [219] have recently shown that MAM is unable to bind directly to TLR2-and TLR4-transfected cells. However, coexpression of TLR2 or TLR4 with HLA-DR significantly increased MAM binding and subsequent T cell stimulation compared to cells expressing HLA-DR alone.…”

Prognostic predictive value of TLR4 polymorphisms in Han Chinese population with hypertrophic cardiomyopathy

“…Toll‐like receptor‐4 ( TLR4 ) is a family member of pattern recognition receptors that play important roles in mediating the inflammatory response [7–9]. TLR4 is mapped to 9q32‐q33 region and contains three exons, which participates in immuno‐regulation by suppressing T lymphocyte proliferation and regulating macrophage function [10–12]. TLR4 has been shown to play an important in the development of cardiovascular diseases [13].…”