Intestinal cDC1s provide IL-12 dependent and independent functions required for CD4⁺T cell-mediated resistance toCryptosporidium

Abstract

Cryptosporidiumis an enteric pathogen that is a prominent cause of diarrheal disease. Control of this infection requires CD4+T cells, though the processes that lead to T cell-mediated resistance have been difficult to assess. Here,Cryptosporidiumparasites that express MHCII-restricted model antigens were generated to dissect the early events that influence CD4+T cell priming and effector function. These studies highlight that parasite-specific CD4+T cells are primed in the draining mesenteric lymph node (mesLN) and differentiate into Th1 cells in the gut, where they mediate IFN-γ-dependent control of the infection. Although type 1 conventional dendritic cells (cDC1s) were not required for initial priming of CD4+T cells, cDC1s were required for CD4+T cell expansion and gut homing. cDC1s were also a major source of IL-12 that was not required for priming but promoted full differentiation of CD4+T cells and local production of IFN-γ. Together, these studies reveal distinct roles for cDC1s in shaping CD4+T cell responses to enteric infection: first to drive early expansion in the mesLN and second to drive effector responses in the gut.SummaryCryptosporidiumparasites that express model antigens were generated to dissect how parasite-specific CD4+T cells are primed and mediate effector functions required to control this enteric pathogen. cDC1s produced IL-12p40 and were required for early expansion and gut homing of CD4+T cells. However, IL-12p40 was only required for the development of Th1 CD4+T cell effector function in the gut.

Analysis of intestinal epithelial cell responses to Cryptosporidium highlights the temporal effects of IFN-γ on parasite restriction

“…Goblet cells, which were infected by Cryptosporidium and had upregulated ISG expression, do not have a well-described role in control of Cryptosporidium , but in other experimental systems have been described to “pass” luminal antigen to local dendritic cells in the small intestine [ 48 ]. As such, the ability to genetically modify Cryptosporidium to express model antigens [ 17 , 49 ] will likely facilitate similar studies on antigen acquisition and presentation by various IEC populations.…”

“…Initial studies using C. parvum identified the importance of T cells and the cytokines IFN-γ, IL-12, and IL-18 for infection control [3,[12][13][14][15]. Subsequently, it has been shown that IL-12 has a crucial role in the polarization of T helper 1 cells [16,17], while local IL-12 and IL-18 drive type 1 innate lymphoid cell (ILC1) and natural killer cells to produce IFN-γ [18]. The dominant role of IFN-γ in the response to Cryptosporidium is evident from infections in mice deficient for this cytokine, which result in high parasite burden and a failure to clear the infection [3,19].…”