TLR2 Stimulation Drives Human Naive and Effector Regulatory T Cells into a Th17-Like Phenotype with Reduced Suppressive Function

Abstract

Naturally occurring CD4+CD25+FOXP3+ regulatory T cells suppress the activity of pathogenic T cells and prevent development of autoimmune responses. There is growing evidence that TLRs are involved in modulating regulatory T cell (Treg) functions both directly and indirectly. Specifically, TLR2 stimulation has been shown to reduce the suppressive function of Tregs by mechanisms that are incompletely understood. The developmental pathways of Tregs and Th17 cells are considered divergent and mutually inhibitory, and IL-17 secretion has been reported to be associated with reduced Treg function. We hypothesized that TLR2 stimulation may reduce the suppressive function of Tregs by regulating the balance between Treg and Th17 phenotype and function. We examined the effect of different TLR2 ligands on the suppressive functions of Tregs and found that activation of TLR1/2 heterodimers reduces the suppressive activity of CD4+CD25hiFOXP3lowCD45RA+ (naive) and CD4+CD25hiFOXP3hiCD45RA− (memory or effector) Treg subpopulations on CD4+CD25−FOXP3−CD45RA+ responder T cell proliferation while at the same time enhancing the secretion of IL-6 and IL-17, increasing RORC, and decreasing FOXP3 expression. Neutralization of IL-6 or IL-17 abrogated Pam3Cys-mediated reduction of Treg suppressive function. We also found that, in agreement with recent observations in mouse T cells, TLR2 stimulation can promote Th17 differentiation of human T helper precursors. We conclude that TLR2 stimulation, in combination with TCR activation and costimulation, promotes the differentiation of distinct subsets of human naive and memory/effector Tregs into a Th17-like phenotype and their expansion. Such TLR-induced mechanism of regulation of Treg function could enhance microbial clearance and increase the risk of autoimmune reactions.

Increased expression of TLR2 in CD4+ T cells from SLE patients enhances immune reactivity and promotes IL‐17 expression through histone modifications

“…The endogenous ligand HMGB1 in circulating DNA-containing immune complexes is crucial for anti-dsDNA antibody induction depending on the TLR2/MyD88/miR-155/Ets-1 pathway [13]. TLR2/TLR1 heterodimer stimulation by Pam3Cys can reduce the suppressive activity of Treg cells and drive naive and effector Treg cells into a Th17-like phenotype [14]. Animal studies showed that when compared to C57BL/6lpr/lpr mice, disease manifestations in TLR2-deficient C57BL/6lpr/lpr mice were less severe accompanied by fewer immunological alterations, less renal lesion, and significantly reduced autoantibody titers [5].…”

TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

“…TLR2 forms heterodimers with either TLR1 or TLR6. The identification of TLRs on T cells, and particularly on Tregs, was an important development in the field of innate immune-regulation of adaptive T cell responses (10,13,23,24). We (10) and others (14,25) demonstrated that TLRs modulate the functions of Tregs.…”

“…The most common approach to defining human Treg subsets is based on combining CD25 and CD127 expression with expression of the classic markers for naive (CD45RA) and memory (CD45RO) conventional T cells (8,9). In addition, based on the expression of CD25 and CD45RA, we (10) and other investigators (8) classified human CD4 + T cells into six subpopulations, fractions (Fr.) I-VI.…”

“…One such proinflammatory stimulus is the cytokine IL-6 (12), which can reduce or abolish the suppressive function of mouse (13) and human (10,14) Tregs. Stimulation of IL-6R leads to activation of several transcription factors, most notably STAT3 (15).…”

Current prospects and future challenges for nasal vaccine delivery

“…Mice immunized with an influenza vaccine adjuvanted with a synthetic TLR-4 agonist via the nasal route, exhibited a transient, enhanced IL-17A pathology, characterized by weight loss and morbidity, which was significantly greater than observed in mice given no-adjuvanted antigen. 41 The effect of adjuvants on induction of tolerance has also been noted; an intranasal co-administration of hen egg lysozyme with a TLR2 ligand enhanced Th1-type antibodies in one case, 118 while another TLG2 ligand, Pam3Cys, was shown to increase the risk of developing autoimmune disease 119 PLGA nanoparticles have been shown to boost tolerance in suppression of arthritis 120 and further research by the same group has shown that they are responsible for generation of enhanced Treg cell induction. 68 …”