Regulation of CD4+ T cells in Cryptosporidium infection

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Project Summary The apicomplexan parasite Cryptosporidium is a leading cause of diarrhea and death in immunocompromised individuals and malnourished children globally. Control of Cryptosporidium requires CD4+ T cells and the cytokine interferon-γ (IFN-γ), however there are significant gaps in our understanding of the regulation of T cell responses against the parasite. This is in large part due to difficulties analyzing T cell populations in the gut. By engineering Cryptosporidium to express MHCII-restricted model antigens, I can identify parasite-specific CD4+ T cells within the gut. Using this system, I have found that CD4+ T cell responses require type 1 conventional dendritic cells (cDC1s) despite their better-studied role in CD8+ rather than CD4+ T cell responses. In addition, I have found evidence for a Th17 response elicited by infection, pointing to an IFN-γ- independent but T cell-dependent mechanism of control of the parasite that has remained elusive. I will utilize a combination of novel transgenic parasites, genetic mouse models, single-cell RNA sequencing, and high- dimensional flow cytometry to test which cDC subset(s) are required for CD4+ T cell responses to Cryptosporidium (SA1), and to investigate the IFN-γ-independent, CD4+ T cell-dependent mechanism(s) of control with a focus on Th17 responses (SA2). These studies will provide an opportunity to train in cross- disciplinary approaches in parasitology and immunology to better understand how immunity to infection in the gut is regulated. The studies proposed here will impact our fundamental understanding of mucosal immunology and drive treatment and prevention for an important source of childhood mortality.