AUTHOR=Antoni Anne-Charlotte , Pylaeva Ekaterina , Budeus Bettina , Jablonska Jadwiga , Klein-Hitpaß Ludger , Dudda Marcel , Flohé Stefanie B. TITLE=TLR2-induced CD8+ T-cell deactivation shapes dendritic cell differentiation in the bone marrow during sepsis JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.945409 DOI=10.3389/fimmu.2022.945409 ISSN=1664-3224 ABSTRACT=

Sepsis is associated with profound immune dysregulation that increases the risk for life-threatening secondary infections: Dendritic cells (DCs) undergo functional reprogramming due to yet unknown changes during differentiation in the bone marrow (BM). In parallel, lymphopenia and exhaustion of T lymphocytes interfere with antigen-specific adaptive immunity. We hypothesized that there exists a link between T cells and the modulation of DC differentiation in the BM during murine polymicrobial sepsis. Sepsis was induced by cecal ligation and puncture (CLP), a model for human bacterial sepsis. At different time points after CLP, the BM and spleen were analyzed in terms of T-cell subpopulations, activation, and Interferon (IFN)-γ synthesis as well as the number of pre-DCs. BM-derived DCs were generated in vitro. We observed that naïve and virtual memory CD8+ T cells, but not CD4+ T cells, were activated in an antigen-independent manner and accumulated in the BM early after CLP, whereas lymphopenia was evident in the spleen. The number of pre-DCs strongly declined during acute sepsis in the BM and almost recovered by day 4 after CLP, which required the presence of CD8+ T cells. Adoptive transfer experiments and in vitro studies with purified T cells revealed that Toll-like receptor 2 (TLR2) signaling in CD8+ T cells suppressed their capacity to secrete IFN-γ and was sufficient to change the transcriptome of the BM during sepsis. Moreover, the diminished IFN-γ production of CD8+ T cells favored the differentiation of DCs with increased production of the immune-activating cytokine Interleukin (IL)-12. These data identify a novel role of CD8+ T cells in the BM during sepsis as they sense TLR2 ligands and control the number and function of de novo differentiating DCs.