TNF and inflammation

Division Of Basic Sciences - Nci

Investigators

Abstract

CD4+ T cells are "skewed" to different "T helper" (Th) fates by activating them in the presence of certain cytokine cocktails. Among the best studied Th subsets are Th1 (master transcription factor: T-bet, signature cytokine: IFN-gamma), Th2 (GATA-3 and IL-4), and Th17 (RORgt and IL-17). Th17 cells can be further roughly divided into non-pathogenic and pathogenic cells. The former express immunosuppressive IL-10 whereas the latter express inflammatory products such as GM-CSF and CXCL3. We have found that when naive CD4+ murine T cells are skewed in the presence of TNF as the primary cytokine they adopt an inflammatory Th17 state. We have used both antibody-blocking and the analysis of knockout mice to determine that TNFR2 (the minor TNF receptor) is responsible for this. In addition, in vivo studies of various autoimmune inflammatory models (e.g. experimental autoimmune encephalopathy (EAE) and colitis due to adoptive transfer of Treg-depleted T cells) with the corresponding TNFR knockout mice have demonstrated a role for TNF signaling in pathological Th skewing. Evaluation of the composition of immune cell infiltrates as well as transcriptomic analysis, both bulk RNA sequencing (RNA-seq) and single cell RNA sequencing (scRNA-seq), has provided a precise picture of how TNF regulation of Th skewing and how it alters the adaptive and innate immune responses. These studies have shown that TNF signaling is upstream of inflammatory Th responses and exacerbates autoimmune/inflammatory diseases. The major and best-studied TNF receptor is TNFR1. We have found that mice deficient in TNFR1 are better able to deal with inflammatory tumors such as pancreatic ductal adenocarcinoma (PDAC). This is due to an enhanced anti-tumor immune response. We are exploring this phenomenon in vivo using mice that spontaneously develop PDAC and are characterizing the innate and adaptive immune response in these animals. Our results indicate that signaling via TNFR1 suppresses the migration and function of antigen-presenting cells in the tumor microenvironment, and its abrogation results in enhanced tumor immunity and survival.