Project Details
Projekt
Molecular analysis of the immune-modulatory properties of colitogenic intestinal microbiota
Applicant
Professor Dr. Kai Hildner
Subject Area
Gastroenterology
Term
from 2016 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 316022883
Batf3 (Basic leucin zipper transcription factor, ATF-like 3) -deficient mice allow studies to assess the specific role of related CD8alpha positive and CD103 positive CD11b negative dendritic cells (DCs) in vivo. Our studies unambiguously revealed a colitis-protective role of Batf3 in the T cell transfer-mediated but not in the Dextran sodiume sulphate (DSS)-induced and anti-CD40-mediated colitis model. Co-housing experiments demonstrated that enhanced transfer colitis susceptibility was transmittable to Batf3-expressing wild type mice and even to Rag1-/- IRF4 (interferon regulatory factor 4)-/- mice usually per se refractory to colitis induction. Also, IL-23R-deficient Tcells normally devoid of colitis-promoting abilities induced colitis in the presence of Batf3-deificiency associated microbiota collectively indicating a dominant functional role of the intestinal microbiota within Batf3-deficient mice in promoting colitis. Finally, the existence of a transmittable dysbiosis in Batf3-deficient mice was formally confirmed by 16s ribosomal RNA gene sequencing analyses. Together, Batf3-dependent DCs appear to be crucial regulators of the intestinal microbiota with tremendous implications for colitis susceptibility and phenotype.Based on our data, we propose the follwoing model. The absence of Batf3-dependent DCs presumably promotes the occurrence of so called pathobionts within the intestinal microbiota that drive T cell and myeloid cell expansion. Specifically, we hypothesize that these communities provide either directly or indirectly (e.g. by inhibiting protective signals derived from other commensals) signals that act in an immune-stimulatory fashion creating an immunological microenvironment that promotes detrimental immune-mediated colitis formation. In the center of the proposed studies is therefore the identification of the colitis-promoting microbial communities, their employed molecular signaling armamentarium, the identification and characterization of the host-derived, microbial signal-receiving machinery and of the cellular and molecular immunological effector mechanisms mediating the detrimental colitis manifestation in the presence of Batf3 deficiency-associated intestinal microbiota.
DFG Programme
Priority Programmes
