CD40 is Required For Protective T Cell Responses Against Cryptosporidium

Abstract

Abstract The apicomplexan intestinal parasite Cryptosporidium infects intestinal epithelial cells (IECs) and is a leading cause of life-threatening disease in infants, toddlers, and immunocompromised patients. No vaccine against Cryptosporidium exists, and current treatments are ineffective in immunocompromised individuals. A prominent immunodeficiency associated with susceptibility to Cryptosporidium is hyper-IgM syndrome, which is caused by defects in CD40 signaling. In a murine model of Cryptosporidiosis, mice deficient in CD154 (CD40L) are defective in parasite control and clearance, and complementation of CD40L restores protection. Therefore, characterizing CD40-mediated immune responses against Cryptosporidium may enhance progress toward effective therapy in at-risk individuals. CD40 engagement on dendritic cells (DCs) promotes IL-12 production that induces differentiation and proliferation of T helper type 1 (Th1) cells and their production of interferon-γ (IFN-γ), which is known to be essential for control and clearance of Cryptosporidium infection. Our findings suggest a defect in T cell responses in CD40−/− mice infected with Cryptosporidium. CD40 deletion on Xcr1+ DCs also resulted in increased susceptibility to Cryptosporidium along with a defect in CD8+ T cell expansion. Therefore, we conclude that CD8+ T cell responses against Cryptosporidium require CD40 on cDC1s. Supported by NIH grant U01AI163671