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Theses Doctoral

The role of intestinal mononuclear phagocytes in control of mucosal T cell homeostasis

Panea, Casandra M.

The intestine is constantly exposed to a wide variety of dietary antigens, commensal bacteria and pathogens, toward which it has evolved complex immune responses to protect the host. The intestinal immune system relies on innate immune cells, such as mononuclear phagocytes (MNPs), that include dendritic cells (DCs), monocytes (Mo) and macrophages (Mfs), to sense and respond to luminal and mucosal challenges. MNPs are essential players as they instruct adaptive immune cells, in particular T cells, to discriminate between innocuous and harmful antigens. Generation of different CD4 T cell responses to commensal and pathogenic bacteria is crucial for maintaining a healthy gut environment, but the associated cellular mechanisms are poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are induced by epithelium-associated commensal segmented filamentous bacteria (SFB). Several reports suggest that the cytokine environment induced by gut bacteria is sufficient to drive LP Th17 cell differentiation. In this context, intestinal DCs are proposed to facilitate the conversion of naïve CD4 T cells to Th17 cells within gut-draining lymph nodes. Whether such mechanisms control commensal-mediated Th17 cell differentiation has not been examined. In this work, I explore the mechanisms of induction of Th17 cells by SFB, with a particular focus on the role of antigen-presenting cells in this process.
Initiation of CD4 T cell responses requires both major histocompatibility II (MHCII)-mediated antigen presentation and cytokine stimulation, which can be provided by the same or different subsets of intestinal MNPs. To test the requirement for either function in the induction of Th17 cells by SFB, we analyzed the role of SFB-induced cytokine environment in driving Th17 cell differentiation of non-SFB transgenic CD4 T cells. We find that although the cytokine environment is important, it is not sufficient to promote Th17 cell differentiation of activated CD4 T cells. In fact, we show that MHCII-dependent antigen presentation of SFB antigens by intestinal MNPs is crucial for Th17 cell induction. Expression of MHCII on CD11c+ cells was necessary and sufficient for SFB-induced Th17 cell differentiation. We also show that most SFB-induced Th17 cells respond to SFB antigens, which stressed that they carry T cell receptors that recognize SFB moieties. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs.
Our results outline the complex role of MNPs in the regulation of intestinal Th17 cell homeostasis, and we investigated the contribution of individual subsets to SFB-specific Th17 cell differentiation. Although the role of DCs in initiating T cell responses is well appreciated, how Mfs contribute to the generation of CD4 T cell responses to intestinal microbes is unclear. To this end, I examined the role of mucosal DCs and Mfs in Th17 induction by SFB in vivo. Employing DC and Mf subset-specific depletion and gain-of-function mouse models, I show that Mfs, and not conventional CD103+ DCs, are essential for generation of SFB-specific Th17 responses. Thus, Mfs drive mucosal T cell responses to certain commensal bacteria.

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More About This Work

Academic Units
Genetics and Development
Thesis Advisors
Ivanov, Ivaylo
Degree
Ph.D., Columbia University
Published Here
July 15, 2016
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