The complex immunological role of Helicobacter in modulating cancer.

The gut microbiota has recently emerged as a unique mechanism of immunotherapeutic resistance or response within certain cancer patients. Certain adherent bacterial species that reside along the epithelial barrier within the gastrointestinal tract have been shown to be the most immunogenic and include several species within the Helicobacteraceae family. The role of these microbes in cancer remains controversial and varies according to species, immune status, and cancer type. Here, we hypothesize that the functional characteristics rather than the bacterial species of Helicobacteraceae dictate the type of immune response with either a benefit or a detriment to overall cancer progression.

Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ.

Major histocompatibility complex class II (MHCII) is dynamically expressed on intestinal epithelial cells (IECs) throughout the intestine, but its regulation remains poorly understood. We observed that spontaneous upregulation of IEC MHCII in locally bred Rag1-/- mice correlated with serum Interleukin (IL)-18, was transferrable via co-housing to commercially bred immunodeficient mice and could be inhibited by both IL-12 and IL-18 blockade. Overproduction of intestinal IL-18 due to an activating Nlrc4 mutation upregulated IEC MHCII via classical inflammasome machinery independently of immunodeficiency or dysbiosis. Immunodeficient dysbiosis increased Il-18 transcription, which synergized with NLRC4 inflammasome activity to drive elevations in serum IL-18. This IL-18-MHCII axis was confirmed in several other models of intestinal and systemic inflammation. Elevated IL-18 reliably preceded MHCII upregulation, suggesting an indirect effect on IECs, and mice with IL-18 overproduction showed activation or expansion of type 1 lymphocytes. Interferon gamma (IFNg) was uniquely able to upregulate IEC MHCII in enteroid cultures and was required for MHCII upregulation in several in vivo systems. Thus, we have linked intestinal dysbiosis, systemic inflammation, and inflammasome activity to IEC MHCII upregulation via an intestinal IL-18-IFNg axis. Understanding this process may be crucial for determining the contribution of IEC MHCII to intestinal homeostasis, host defense, and tolerance.