Microbial Regulation of Retinol Transport and its Role in Intestinal Immunity

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Project Summary The intestinal epithelium regulates the development of adaptive immunity to gut microorganisms, yet little is known about the underlying mechanisms. Filling this knowledge gap is crucial, as many human intestinal diseases arise from dysregulated intestinal immunity. Dietary vitamin A absorbed by the intestinal epithelium is essential for key adaptive immune responses to the microbiota. These include the homing of CD4+ T cells to the intestine and the development of B cells that produce immunoglobulin A. These responses depend on specialized intestinal dendritic cells (DCs) that enzymatically convert the vitamin A derivative retinol to retinoic acid (RA). A major unanswered question is how RA-producing DCs acquire their retinol. Retinol's lipid-like chemical nature necessitates its transport by proteins that protect the retinol from the aqueous environment. However, the protein(s) that mobilize retinol from the intestinal epithelium to DCs as substrate for RA production remain unknown. We have gained insight into this question by studying serum amyloid A (SAA) proteins, which are produced by the intestinal epithelium in response to the microbiota. This R01 renewal application will explore the hypothesis that serum amyloid A (SAA) proteins mobilize retinol to RA-producing DCs and thus shape intestinal adaptive immunity. In the previous project period, we discovered that SAAs are retinol-binding proteins that circulate with bound retinol during acute systemic infection. Further preliminary findings indicate that intestinal SAAs promote retinol acquisition by RA-producing DCs. We propose to build on these findings during the next project period to gain a deeper mechanistic understanding of how SAAs shape intestinal DC function and the development of intestinal adaptive immunity. In Aim 1, we will delineate the role of SAAs in retinol acquisition and retinoic acid production by intestinal dendritic cells. In Aim 2, we will identify the cellular receptor for retinol-bound SAAs. In Aim 3, we will determine the physiological relevance of SAAs for the development of vitamin A-dependent adaptive immunity in the intestine. These studies will provide mechanistic insight into how vitamin A is mobilized to intestinal immune cells and advance our understanding of how microbiota-epithelial interactions shape adaptive immunity. Understanding how the microbiota controls vitamin A-dependent immunity will promote the design of new therapeutics for inflammatory disorders and vaccines against infections.