Journal Article

Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner

Amon, Lukas, Khan, Hanif, Konein, Patrick, Lehmann, Christian H. K., Wirtz, Stefan, Neufert, Clemens, Hildner, Kai, Büttner-Herold, Maike, Buchele, Vera, Enderle, Karin, Kunert, Timo, Vogler, Tina, Neurath, Markus F., Dudziak, Diana

2021

Overview

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo . Employing the CD4 + CD25 − naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1 −/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1 −/− but not in colitis-protected Rag1 −/− Irf4 −/− mice. Colitis mitigation in Rag1 −/− Irf4 −/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1 −/− Irf4 −/− T cell receiving mice.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / CD25 antigen / CD4 antigen / Cdc2 protein / Cell differentiation / Colitis / Colitis - immunology / Colitis - pathology / Colon / Colon - pathology / Cytokines / Dendritic cells / Disease / Disease control / Helper cells / Homeodomain Proteins - genetics / Homeodomain Proteins - immunology / Immunology / Immunosuppressive agents / Inflammation / Inflammatory bowel disease / inflammatory bowel disease (IBD) / Inflammatory bowel diseases / Interferon / Interferon regulatory factor / Interferon regulatory factor 4 / interferon regulatory factor 4 (IRF4) / Interferon Regulatory Factors - genetics / Interferon Regulatory Factors - immunology / intestinal inflammation / Intestine / Laboratories / Lamina propria / Lymph nodes / Lymphocytes / Lymphocytes T / Mice / Mice, Inbred C57BL / Mice, Transgenic / Molecular modelling / myeloid cells / RAG1 protein / T-Lymphocytes - immunology / T-Lymphocytes - transplantation / Th17 / Transcription factors