T cell receptor signaling and Toll-like receptor signaling converge to amplify T cell responses

Abstract

Abstract Toll-like receptors (TLRs) are an essential part of the innate immune system. Their function on antigen presenting cells helps drive efficient T cell responses to pathogens. However, T cells also express several TLRs. Additionally, many of the downstream signaling components of TLRs are shared with those of the T cell receptor. Our hypothesis is that these two pathways work in concert to exert unique and potent T cell responses. We have found that several TLRs are able to enhance T cell responses, including TLR3, TLR4, TLR7, and TLR9. We have found that TLR7 signaling, in particular, synergizes with TCR activation and improves T cell effector functions. Priming T cells with synthetic and natural TLR7 ligands before TCR ligation further boosts T cell responses. The combination of TLR7 and TCR stimulation in T cells enhances cytokine production and proliferation in T cells. We identified several overlapping components between TLR7 and TCR activation pathways by gene expression, which may provide combinatorial increases in T cell activation. In addition, we found increases in anti-viral response pathways that are atypical in T cells. This response was unique to the combination of TLR and TCR stimuli. Thus, we wanted to determine if TLR7 signaling in T cells is important during an acute infection. During influenza, T cell-specific loss of TLR7 alters infection dynamics in the T cell population, resulting in significant activation delays and abnormalities. These findings show that TLR7 is important in normal T cell responses to viral infections. Understanding the contribution of TLR signaling to T cell activation will be useful in guiding enhanced vaccine strategies.