Research Article: T cell-intrinsic TLR2 stimulation promotes IL-10 expression and suppressive activity by CD45RbHi T cells

Date Published: July 25, 2017

Publisher: Public Library of Science

Author(s): Janice C. Jun, Mark B. Jones, Douglas M. Oswald, Edward S. Sim, Amruth R. Jonnalagadda, Lori S. C. Kreisman, Brian A. Cobb, Frederic Rieux-Laucat.


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.

Partial Text

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. For nearly two decades, TLRs have been the subject of intense study for their role in ‘pattern recognition’ and the induction of the inflammatory response by neutrophils, macrophages, and other leukocytes [1,2]. It is also well-appreciated that TLR stimulation can have potent, albeit indirect, effects on the downstream adaptive response through the promotion of cytokine, chemokine, and other mediator secretion from activated leukocytes. As such, the impact of TLR signaling upon the adaptive response is driven by the intrinsic antigen presenting cell (APC) and local leukocyte response.

While TLRs have been primarily studied in innate-associated leukocyte activation, growing evidence suggests that these receptors are expressed in CD4+ T cells and intrinsically alter their behavior upon stimulation. TLR2 is of particular interest because of its reported and apparently unique ability to modulate the activity of Treg cells, which are key components in the maintenance of homeostasis and health. In this study, we demonstrate that simultaneous stimulation of TLR2 and TCR produces a profound increase in IL-10 production that is able to inhibit bystander T cell activation. In contrast to previous reports which report TLR2-mediated stimulation of FoxP3+ Tregs, we discovered that this effect occurs only in CD44+FoxP3- T cells, and leads to the expansion of a CD4+CD25+CD62L-CD44+CD45Rbhi Tem population that is not typically associated with suppressive activity. Although we do not yet know why our results contradict previous reports on the role of FoxP3+ Tregs in TLR2-mediated immune modulation [8,18,20], our study utilizes individual cell detection with fluorescence reporting for both IL-10 and FoxP3 simultaneously, providing a greater degree of confidence in the cellular identity. Moreover, we found that IL-2 is reduced in cells stimulated with both TCR and TLR2 signals, which may support previous reports in which TLR2 stimulation served only as a survival signal for FoxP3+ Tregs but did not change their suppressive activity [22]. In any case, our findings support a model in which TLR2 represents a class of co-regulatory molecules on antigen-experienced, non-Treg cells which alters canonical TCR stimulation by enhancing IL-10 secretion.




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