Abstract
While Toll-like receptors (TLRs) represent one of the best characterized innate immune pathways, evidence suggests that TLRs are not restricted to innate leukocytes and some epithelial cells, but are also expressed in T cells. Specifically, published evidence focusing on FoxP3+ regulatory T cells demonstrate that they express functional TLR2, which is already known among the TLR family for its association with immune suppression; however, little is known about the relationship between T cell-intrinsic TLR2 binding and cytokine production, T cell differentiation, or T cell receptor (TCR) stimulation. Here, we demonstrate that TCR and TLR2 co-stimulation provides a T cell-intrinsic signal which generates a dramatic, synergistic cytokine response dominated by IL-10. Importantly, the response was not seen in either CD4+CD25+ or CD4+FoxP3+ Tregs, yet resulted in the expansion of a suppressive CD4+CD25+CD62L-CD44+CD45Rbhi effector/memory T cell subset not typically associated with immune inhibition. This study reveals the striking ability of a prototypical innate immune receptor to trigger a potent and suppressive IL-10 response in effector/memory T cells, supporting the notion that TLR2 is a co-regulatory receptor on T cells.
Highlights
The prototypical innate immune receptor family is the Toll-like receptors (TLRs)
In contrast to previous work focused on CD25+ and FoxP3+ Tregs, we found that T cell receptor (TCR) and TLR2 co-stimulation occurs preferentially in CD4+CD25- and CD4+FoxP3- T cell subsets, while promoting the expansion of CD4+CD25+CD62L-CD44+CD45Rbhi effector/memory T cells (Tem) which produce high concentrations of IL-10
In order to define the role of TLR2 stimulation in T cell responses, CD4+ T cells were harvested from IL-10-IRES-eGFP reporter mice spleens by positive magnetic bead sorting, and stimulated with plate-bound αCD3 (2μg/ml), the TLR2/1-skewed agonist Pam3Csk4 (P3C; 2μg/ml), or both for 3 days and compared to unstimulated controls. eGFP-positive cells were quantified by flow cytometry
Summary
The prototypical innate immune receptor family is the Toll-like receptors (TLRs). These cell surface glycoproteins recognize molecular ‘patterns’ ranging from lipopolysaccharide and peptidoglycan to host-encoded heat-shock proteins, and are highly expressed by cells within the myeloid lineage. TLR2 engagement in both macrophages and dendritic cells has been found to mediate IL-10 production, a cytokine strongly associated with a regulatory response [14,15] The result of such stimulation has been shown to suppress the immune system [16], which holds serious implications for host defenses against pathogens such as Mycobacterium tuberculosis [17], Candida albicans [18], and pathogenic Yersinia species [19]. An endogenous TLR2 ligand has been shown to enhance Treg function [23], and this correlation is supported by an in vivo study showing functionally significant TLR2-driven Treg expansion in an ovalbumin-based acute asthma model [24] Despite these reports, little is known about the relationship between T cell-intrinsic TLR2 stimulation and IL-10 production, the potential for different TLR2-containing dimers (i.e., TLR1/2, TLR2/ 2, and TLR2/6) to impact these observations, T cell differentiation, or TCR stimulation within responding T cells. The stimulation of TLR2 appears to promote a unique, cell-intrinsic differentiation and cellular response program in CD45RbHi effector/memory T cells not typically associated with a regulatory phenotype
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