We propose that retinoic acid (RA) regulates mucosal adaptive immune response controlling the fate of committed (Th1, Treg, CD8eff) T cells. In the absence of RA signaling, we show that RA, through its receptor RAR?, sustains stable expression of Th1 lineage specifying genes as well as repressing genes that instruct Th17 cell fate. Our studies identify RA-RAR? as a key component of the regulatory network governing Th1 cell fate and define a new paradigm of Th1a?Th17 differentiation. These findings have important implications for gut immunity in which dysregulated Th1-Th17 responses are observed. We further show that ablation of RA signaling in the Foxp3 lineage ablates in vivo Treg function. Finally, impairment of RA signaling of through specific receptor isoforms limits CD8 T cell survival and differentiation. As such, we propose that these functions of RA are prominent in its role in host resistance to infectious disease. Using genetic models that allow lineage specific control of RA signaling in vivo we will: 1. Define the role of RA in Th1 stability and repression of Th1a?Th17 differentiation in the gut in vivo. We show that RA controls the level of T-bet expression in Th1 T cells and as such controls Th1 lineage maintenance. Furthermore, we show that T cells which are deprived of an RA signal develop into double positive, IL17+, IFNgLow T cells and Th17 cells. RARa CHIPseq studies and transcriptome analysis have identified for the first time, direct targets for RAR regulation in T cells and provie important biological leads as to how RA programs T cell lineage maintenance and phenotype. Finally, given the fact that RA tissue levels control critical events in T cell commitment, we will exploit the use of genetic models where RA synthesis can be specifically ablated in the lineage of choice to determine the RA-synthesizing cells that support T cell fate in vivo. 2. Define the role of RA in sustaining Treg function in the gut. Selective silencing of RA signaling in the Foxp3 lineage, results in the emergence of a striking inflammatory syndrome that we hypothesize is due to Treg lineage instability and dysfunction. It is proposed that both natural and adaptive Treg function is ablated and the underlying cellular and molecular mechanisms will be addressed. 3. Understanding the role of RA in CD8 lineage commitment in the gut. We have defined specific distinctive contributions of RARa vs RARb in CD8 T cell biology. In CD8+ T cells, RARa is critical for T cell survival and RARb is critical for antigen-specific T cell expansion. These approaches provide the novel and exciting opportunity to fully define the role of RAR isoforms in CD8+ T cell stability, survival, expansion and development of memory. A comprehensive set of studies is presented which will represent the first to track and quantify the antigen-specific CD8+ T cell responses in the gut.

Public Health Relevance

Vitamin A, acting through it's metabolite, retinoic acid, is key to a healthy immune response to defend against infection. This proposal dissects the exact role that retinoic acid serves in the induction of an integrated and effective immune response in the gut. Many of the pathogens we encounter enter through the gut, yet immunity at mucosal sites is poorly understood. This work will reveal the role of retinoic acid in gut immunity, and pave the way for new therapies that can improve mucosal immunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Rothermel, Annette L
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Dartmouth College
Schools of Medicine
United States
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Chandraratna, Roshantha As; Noelle, Randolph J; Nowak, Elizabeth C (2016) Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimmune encephalomyelitis. Am J Transl Res 8:1016-26
Brown, Chrysothemis C; Esterhazy, Daria; Sarde, Aurelien et al. (2015) Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 42:499-511
Brown, Chrysothemis C; Noelle, Randolph J (2015) Seeing through the dark: New insights into the immune regulatory functions of vitamin A. Eur J Immunol 45:1287-95