Toll-like receptor-2/7-mediated T cell activation: An innate potential to augment CD8+ T cell cytokine production

CD8(+) T cells are critical to combat pathogens and eradicate malignantly transformed cells. To exert their effector function and kill target cells, T cells produce copious amounts of effector molecules, including the pro-inflammatory cytokines interferon gamma, tumour necrosis factor alpha and interleukin 2. TCR triggering alone is sufficient to induce cytokine secretion by effector and memory CD8(+) T cells. However, T cells can also be directly activated by pathogen-derived molecules, such as through the triggering of Toll-like receptors (TLRs). TLR-mediated pathogen sensing by T cells results in the production of only interferon gamma. However, in particular when the antigen load on target cells is low, or when TCR affinity to the antigen is limited, antigen-experienced T cells can benefit from costimulatory signals. TLR stimulation can also function in a costimulatory fashion to enhance TCR triggering. Combined TCR and TLR triggering enhances the proliferation, memory formation and effector function of T cells, resulting in enhanced production of interferon gamma, tumour necrosis factor alpha and interleukin 2. Therefore, TLR ligands or the exploitation of TLR signalling could provide novel opportunities for immunotherapy approaches. In fact, CD19 CAR T cells bearing an intracellular TLR2 costimulatory domain were recently employed to treat cancer patients in a clinical trial. Here, the current knowledge regarding TLR2/7 stimulation-induced cytokine production by T cells is reviewed. Specifically, the transcriptional and post-transcriptional pathways engaged upon TLR2/7 sensing and TLR2/7 signalling are discussed. Finally, the potential uses of TLRs to enhance the anti-tumor effector function of T cells are explored.