Date of Award
Doctor of Philosophy (PhD)
The gastrointestinal tract has evolved in the context of continuous exposure to both commensal organisms as well as dietary intake. While the impact of commensal organisms on the immune system has been well studied, the effects of dietary factors in the control of intestinal immunity remain unclear. Moreover, the immunologic effects of vitamin deficiencies and are poorly understood. Using a mouse model of dietary vitamin A deficiency, we investigated mechanisms by which the principle vitamin A metabolite, retinoic acid, regulates several aspects of innate immunity. In Chapter 1 we present the hypothesis that the homeostasis of innate cells in the GI tract is dominantly regulated by dietary vitamin A. In Chapter 2 we explore both the function of intestinal eosinophils in the GI tract and the role of vitamin A in supporting their unique intestinal functionalities. Chapter 3 highlights the dependence of CD103+ dendritic cells on dietary vitamin A for their homeostasis in the GI tract. As well, we find that CD103+ DCs require retinoic acid receptor alpha (RARa) for their production of retinoic acid. In Chapter 4 we demonstrate that vitamin A regulates an inverse balance between innate lymphoid cell (ILC) subsets by promoting IL-22 producing ILC3 while directly suppressing IL-13 producing ILC2. Consequently, Vitamin A deficiency results in impaired immunity against bacterial infection and a reciprocal increase in type 2 responses to worm infection. Chapter 5 presents a unified model of gastrointestinal innate immunity during vitamin A deficiency and it implications for understanding intestinal barrier defense during malnutrition as well as during normal immune homeostasis. Further, we hypothesize that RA serves as a indicator of nutrient status and that RARa signaling may be required for most immune cells to achieve full inflammatory/proliferative potential. Thus, ILC2 may be unique in their metabolic requirements, allowing them to persist and function in states of nutrient deprivation. Thus, in vitamin A deficiency, a switch to innate type 2 immunity may represent a powerful adaptation of the immune system to promote host survival in the face of ongoing barrier challenges and the immune deficits discussed in the previous chapters.
Spencer, Sean Paul, "Regulation of Intestinal Innate Immunity by Dietary Vitamin A" (2013). Publicly Accessible Penn Dissertations. 930.