Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells.

Abstract

Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4+ TH1 cells during mucosal responses to the protozoan parasite Toxoplasma gondii results in dysbiosis and the elimination of Paneth cells. Paneth cell death led to loss of antimicrobial peptides and occurred in conjunction with uncontrolled expansion of the Enterobacteriaceae family of Gram-negative bacteria. The expanded intestinal bacteria were required for the parasite-induced intestinal pathology. The investigation of cell type-specific factors regulating TH1 polarization during T. gondii infection identified the T cell intrinsic TLR pathway as a major regulator of IFN-γ production in CD4+ T cells responsible for Paneth cell death, dysbiosis and intestinal immunopathology.