Editors' ChoiceImmunology

TLR2 Stimulates Th1 Effector Functions

Science's STKE  29 May 2007:
Vol. 2007, Issue 388, pp. tw185
DOI: 10.1126/stke.3882007tw185

Toll-like receptors (TLRs) are pattern-recognition receptors that recognize microbial products and are crucial components of the innate immune system. TLR ligands have costimulatory roles with stimulation of the T cell antigen receptor (TCR) of naïve CD4+ T cells (although TLR ligands alone cannot stimulate naïve cells), but the actions of TLR ligands on established effector (memory) T cells are poorly understood. T helper (Th) cells are distinct lineages of memory CD4+ T cells. Th1 cells secrete the effector cytokine interferon-γ (IFN-γ) and are important in the immune response to intracellular pathogens, whereas Th2 cells secrete interleukin-4 (IL-4) and protect against infection by extracellular pathogens. Imanishi et al. investigated the effects of TLR ligands on mouse Th1 and Th2 cell cultures established after TCR stimulation of naïve CD4+ T cells under the appropriate conditions. When Th1 cells were restimulated with various TLR ligands, only the TLR2 ligands MALP-2 (macrophage-activating lipopeptide 2) and Pam3 [N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-Cys-Ser-Lys4] stimulated the secretion of IFN-γ, as measured by enzyme-linked immunosorbant assay. TLR2 stimulation also resulted in the activation and proliferation of Th1 cells. In contrast, TLR2 stimulation of Th2 cells did not increase IL-4 secretion or cause cellular activation. TLR2-mediated production of IFN-γ also occurred in Th1 cells that were treated with the TCR inhibitor cyclosporine A, indicating that TCR signaling was not necessary for IFN-γ production. Western blot analyses demonstrated that Pam3 treatment of Th1 cells, but not Th2 cells, resulted in strong and sustained activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Activation of these pathways by TLR2 requires the adaptor molecule MyD88 and IRAK4 (IL-1 receptor-associated kinase 4). Th1 cells from mice deficient in either MyD88 or IRAK4 did not secrete IFN-γ after TLR2 stimulation. The secretion of IFN-γ by Th1 cells after stimulation with Pam3 was enhanced by either IL-2 or IL-12, and these effects were mediated by enhanced MAPK activation. Together, these data establish TLR2 as a direct stimulator of Th1 functions and suggest that TLR2 signaling differs in naïve and memory CD4+ T cells.

T. Imanishi, H. Hara, S. Suzuki, N. Suzuki, S. Akira, T. Saito, Cutting Edge: TLR2 directly triggers Th1 effector functions. J. Immunol. 178, 6715-6719 (2007). [PubMed]