TLRs deliver a direct hit to T_H17 cells

Toll-like receptors (TLRs) generally promote adaptive immune responses indirectly by activating innate immune cells. Now, new research shows an unexpected direct role for TLR2 signalling in T cells themselves, promoting the differentiation and proliferation of T helper 17 (T_H17) cells.

Microarray and flow cytometry analyses of various T cell subsets showed that T_H17 cells express high levels of TLR2 and its dimerization partners, TLR1 and TLR6, with levels being higher than in T_H1 and T_H2 cells but lower than in macrophages and interleukin-17 (IL-17)-producing γδ T cells. In support of a functional role for TLR expression in T cells, purified naive CD4⁺ T cells cultured in T_H17-polarizing conditions in the presence of the TLR2 agonist Pam3Cys-Ser-Lys4-trihydrochloride (Pam3CSK4) showed a marked increase in IL-17 production, as well as upregulation of mRNA encoding the T_H17 cell-associated transcription factors retinoic acid receptor-related orphan receptor-γ (RORγ) and interferon-regulatory factor 4 (IRF4). Pam3CSK4 had no effect in cultures of Tlr2^−/− T cells.

In addition to directly promoting T_H17 cell differentiation, the authors showed that TLR2 activation in naive T cells, T_H17 cells, memory T cells and γδ T cells enhanced their proliferation in vitro, even in the absence of T cell receptor stimulation. IL-23 was found to synergize with TLR2 agonists in the proliferation of these subsets, as well as in the production of IL-17 by T_H17 cells.

To explore the role of TLR2 signalling in the regulation of T_H17 cells in vivo, the authors reconstituted immunodeficient mice with wild-type or Tlr2^−/− CD4⁺ T cells and injected them with myelin oligodendrocyte glycoprotein in complete Freund's adjuvant to induce experimental autoimmune encephalomyelitis (EAE). Surprisingly, compared with mice reconstituted with wild-type T cells, mice receiving Tlr2^−/− T cells were largely resistant to EAE induction, showing much reduced cellular infiltration of the central nervous system with fewer cells producing IL-17 or interferon-γ.

So, in addition to the well known role of TLR signalling in the activation of innate immune cells, TLR2 ligands can act directly on T cells and modify adaptive immune responses that contribute to the pathogenesis of autoimmune disease.