How Microbiota Shape the Immune System

The Presenter

Andreas Radbruch, PhD
Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin

Session Summary

Recent evidence shows that distinct bacteria of the microbiota can imprint the immune system of their host decisively, evading immune reactions of their host, and exploiting them against their competitors. Segmented filamentous bacteria, for instance, have been shown to direct T cell differentiation toward Th17 and T follicular helper (Tfh) cell pathways, in immune responses against Citrobacter. In the physiological state, bacteria of the microbiota are exposed to the immune system, but regulatory T cells maintain tolerance. If physiological regulation is impaired, naïve Th cells are activated by microbial antigens, and initiate intestinal inflammation. Even if they start out as Th17 cells, in the end the activated Th cells develop into pro-inflammatory Th1 cells, as we can show by sorting viable Th cells according to cytokine expression ex vivo, for adoptive transfer. In positive feedback loops the activated Th1 cells orchestrate a “type 1” inflammation, by attraction and activation of M1 macrophage/monocytes and granulocytes. The Th1 cells adapt to chronic inflammation by expressing the transcription factor Twist1. The “chronicity gene” Twist1 induces expression of about 70 genes in the pro-inflammatory Th1 cells, genes which control their survival, metabolism, and inflammatory competence.

Originally, it had been described that Th cells require T-bet, the “master transcription factor” of Th1 cells, to be able to induce colitis. Surprisingly, we now can identify distinct microbiotic bacteria, which license T-bet deficient Th cells to induce colitis. These T-bet deficient Th cells induce a “type 2” inflammation, characterized by M2 macrophages. In a personalized approach to patients with inflammatory bowel disease, profiling of the individual microbiota from feces, for bacteria licensing distinct types of inflammation, will provide a non-invasive, fast, and efficient diagnostic tool. “High-Resolution Microbiota Cytometry” can visualize the dramatic changes of microbiota composition in inflammatory bowel diseases, fast and efficiently, and isolate distinct bacteria for functional and molecular analyses. Physiological tolerance of the mucosal immune system is maintained by Th cells expressing the cytokines interleukin-10 and/or “Transforming Growth Factor beta” (TGF-ß). TGF-ß is also the cytokine targeting antibody class switch recombination to immunoglobulin A (IgA) in activated B lymphocytes, the predominant class of mucosal antibodies, able to neutralize pro-inflammatory bacteria.

By serendipity, we have identified a distinct bacterial species of murine microbiota, which induces TGF-&[beta] in intestinal T follicular helper cells, and IgA secreting plasma cells in the lamina propria of the small intestine, resulting in significantly increased mucosal IgA production. This anti-inflammatory bacterium is also present in the microbiota of humans, and its presence correlates to levels of mucosal IgA there.

CMLE Credit: 0.5