The Interplay of Antigen Presenting Cells, Microbiota, and IL-17 Producing T cells in Intestinal Health and Colorectal Cancer
Date
2022
Authors
Advisors
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Abstract
The intestine is the home for trillions of microbes, collectively called microbiota. The mutualism of commensal microbes benefits intestinal health. To establish mutualism, intestinal immunity must equip with mechanisms to tolerate innocent microbiota while responding to pathogens. Intestinal immunity is coordinated by specialized and complicated mononuclear phagocytes subsets. The constitution of complex mononuclear phagocytes are thought to be similar in both small intestine and colon, however, these two organs are distinct in anatomy, microbiota abundance and composition, and immunological requirement. However, whether those distinctions require organ-specific mononuclear phagocytes to exert organ-specific immunity is unknown. To address whether there are organ-specific demands, we implement a novel mononuclear phagocyte subsetting strategy in the murine intestine and found two novel colon-specific mononuclear phagocytes: a macrophage population and a Th17-inducing dendritic cell (DC) subset. Those colon-specific DCs and macrophages surprisingly both required the transcription factor IRF4 and co-expressed DC marker CD24 and macrophage marker CD14. Novel IRF4-dependent CD14+CD24+ macrophages were markedly different from conventional macrophages in the way that novel CD14+CD24+ macrophages did not express macrophage markers CX3CR1, CD64, and CD88, and surprisingly not expressed cytokine IL-10, which is known to expressed in intestinal macrophages. Furthermore, we found that novel colon-specific CD14+CD24+ mononuclear phagocytes promote Th17 immunity in the colon and showed definitive evidence of differential requirement of mononuclear phagocytes in small intestine and colon for Th17 immunity. Our research discovered the diversity of mononuclear phagocytes with organ specificity and the organ-specific requirements for Th17 immunity.
While we found the requirement of organ-specific mononuclear phagocytes for Th17 immunity, regulation of innate-like IL-17 producing gd T cells, constituting a large source of IL-17 in intestine, is not addressed. It has been widely known that effector functions of gd T cells were pre-committed in the thymus, however, emerging evidence shows that environmental cues further re-programed gd T cell effectors. In the intestine, the major environmental cues are derived from the microbiota. Nevertheless, the microbiota-dependent regulation is controversial that some reports hold that microbiota provide immune activation signals while other reports conclude the suppressive function of microbiota. It remains unknown whether the impact of microbiota on gd T cells is activated, suppressive, or binary and whether microbiota shape gd T cells immune dynamics in distinct physiological conditions. Here, we identify that microbiota concomitantly upregulate IL-17-production and expression of the inhibitory receptor programmed cell death protein (PD-1) in gd17 T cells. The requirement of microbiota to preferentially upregulate PD-1 is conserved in gd17 T cells across multiple mucosal tissues. We determined the microbiota-driven PD-1 inhibits IL-17 production by endogenous gd17 effectors. We further show that microbiota-driven PD-1 and IL-17 phenotype are dynamics, wherein both PD-1 and IL-17 are downregulated once microbiota is depleted and is concomitantly upregulated during gut inflammation. Additionally, we found subset-specific metabolic shift in gd17 T cells that elevated lipid uptake in gd17 cells in response to intestinal inflammation linking to enhanced IL-17 production.
The coordination between adaptive and innate immune responses is essential for eradicating cancer cells. Among immune cells, DCs are the most powerful cells connecting innate and adaptive immune responses. Especially, Batf3-dependent DCs subset are thought to be key to anti-tumor immunity. The anti-tumor functions of Batf3-dependent DCs have been well reported in skin cancer, however, whether these DCs have the similar anti-tumor functions in colorectal cancer is largely unknown. Here, we investigated the roles of Batf3-dependent DCs in a spontaneous colorectal cancer and surprisingly found that these DCs promoted colon tumorigenesis. We identified an unconventional function of Batf3-dependent DCs to promote tumor infiltrating gd17 T cells in colon tumor instead of expanding anti-tumor IFNg-producing T cells. Proinflammatory cytokine IL-17 is known to promote colon tumor and the pro-tumor role of gd17 T cells have been proposed in several cancers including colorectal cancer. Mechanistically, we determined that Batf3-dependent DCs promote recruitment of gd17 T cells in colon tumor but are not required for gd17 T cells survival or proliferation. As we found that microbiota drives IL-17 production in gd17 T cells, the production of tumor infiltrating endogenous effector gd17 T cells and colon tumor growth were microbiota-dependent. Our study revealed a requirement of Batf3-dependent DCs to regulate tumor infiltrating gd17 T cells and the effector function is modulated by microbiota in colon tumor.
Type
Department
Description
Provenance
Citation
Permalink
Citation
Huang, Hsin-I (2022). The Interplay of Antigen Presenting Cells, Microbiota, and IL-17 Producing T cells in Intestinal Health and Colorectal Cancer. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25193.
Collections
Except where otherwise noted, student scholarship that was shared on DukeSpace after 2009 is made available to the public under a Creative Commons Attribution / Non-commercial / No derivatives (CC-BY-NC-ND) license. All rights in student work shared on DukeSpace before 2009 remain with the author and/or their designee, whose permission may be required for reuse.