The microbiome determines the phenotype in CTLA-4 insufficient mice and men

CTLA-4 (haplo)insufficiency displays incomplete penetrance and phenotypic heterogeneity, indicating the involvement of additional disease modifiers beyond the genetic defect. Microbiome analyses reveal a positive association between disease severity and intestinal dysbiosis, highlighting the microbiome as a critical contributor. To investigate this relationship mechanistically, we generated Ctla4/- wildlings harboring a natural microbiota. Unlike specific pathogen free (SPF) counterparts, which remain healthy, Ctla4/- wildlings spontaneously develop disease phenotypes resembling human CTLA-4 haploinsufficiency. Disease onset is followed by reduced microbial diversity and expansion of pathobionts. Integrative immunophenotyping shows that the natural microbiota synergizes with Ctla4 haploinsufficiency to reshape innate and adaptive immune compartments, generating a sustained pro-inflammatory milieu and reduced CTLA-4 expression in the cecum. Furthermore, microbiota-derived metabolites promote inflammatory cytokine production in both murine and human primary T cells via NF-{kappa}B activation. Collectively, Ctla4/- wildlings constitute an effective model for dissecting microbiome-immune crosstalk in CTLA-4 (haplo)insufficiency and for exploring therapeutic strategies.