NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth

Inflammatory bowel diseases involve the dynamic interplay of host genetics, microbiome and inflammatory response. Here, we report that NLRP12, a negative regulator of innate immunity, is reduced in human ulcerative colitis by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12-deficiency in mice caused increased colonic basal inflammation, leading to a less-diverse microbiome, loss of protective gut commensal strains (Lachnospiraceae) and increased colitogenic strains (Erysipelotrichaceae). Dysbiosis and colitis susceptibility associated with Nlrp12-deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines or by administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from specific pathogen free reared mice into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contribute to immune signaling that culminates in colon inflammation. These findings reveal a feed-forward loop where NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12-deficiency can reverse dysbiosis

Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner

Murine invariant natural killer T (iNKT) cells provide cognate and non-cognate help for lipid and protein-specific B cells, respectively. However, the long term B cell outcome following cognate iNKT help is currently unknown. We show that cognate iNKT cell help resulted in a B cell differentiation program characterized by extrafollicular plasmablasts, germinal center formation, affinity maturation and a robust primary IgG antibody response that was uniquely dependent on iNKT-derived interleukin 21 (IL-21). However, cognate iNKT cell help did not generate an enhanced humoral memory response. Thus, iNKT cell cognate help for lipid-specific B cells induces a unique signature which is a hybrid of classic T-dependent (TD) and T-independent type 2 (TI-2) B cell responses