Innate Immune Defenses Mediated by Two ILC Subsets Are Critical for Protection against Acute Clostridium difficile Infection

Infection with the opportunistic enteric pathogen Clostridium difficile is an increasingly common clinical complication that follows antibiotic treatment-induced gut microbiota perturbation. Innate lymphoid cells (ILCs) are early responders to enteric pathogens; however, their role during C. difficile infection is undefined. To identify immune pathways that mediate recovery from C. difficile infection, we challenged C57BL/6, Rag1(-/-) (which lack T and B cells), and Rag2(-/-) Il2rg(-/-) (Rag gamma c(-/-)) mice (which additionally lack ILCs) with C. difficile. In contrast to Rag1(-/-) mice, ILC-deficient Rag gamma c(-/-) mice rapidly succumbed to infection. Rag1(-/-) but not Rag gamma c(-/-) mice upregulate expression of ILC1-or ILC3-associated proteins following C. difficile infection. Protection against infection was restored by transferring ILCs into Rag gamma c(-/-) mice. While ILC3s made a minor contribution to resistance, loss of IFN-gamma or T-bet-expressing ILC1s in Rag1(-/-) mice increased susceptibility to C. difficile. These data demonstrate a critical role for ILC1s in defense against C. difficile.