Vitamin A deficiency results in pathological alterations in immunity. Only in the last year, has it been shown that retinoic acid (RA), a Vitamin A metabolite, dramatically enhances the differentiation of effector, CD4+ T cells (Teff)AECD4+, adaptive regulatory T cells (aTreg). Given this realization, the profound importance of Treg to human health and disease, and the powerful impact that RA exerts on the growth and differentiation of these cells, we hypothesize that the actions of RA on Treg growth, differentiation and function is central to the impact of Vitamin A on immunity. This proposal will discover the underlying molecular, cellular and immunologic consequences of Vitamin A deficiency and supplementation on the differentiation of Treg and peripheral immunologic tolerance.
The Specific Aims will determine: 1) The molecular mechanisms which control RA-induced differentiation of Teff AETreg. We have shown that RA dramatically enhances the frequency of aTreg. Preliminary findings indicate that RAR? and RXR? are the critical receptors for the induction of Treg. The role of these receptors in Treg function will be determined using specific inhibitors and agonists for RAR/RXR, as well as T cells that are genetically impaired in RAR/RXR signaling. We also hypothesize that RA induces the differentiation of Treg to an "effector" Treg by virtue of differential gene expression, altered cytokine production, homing and an irreversible commitment to the Treg lineage. 2) The in vivo impact of Vitamin A depletion and supplementation on the development of peripheral T cell tolerance. In a model of Treg -dependent allograft tolerance, Vitamin A deficiency results in loss of tolerance and graft rejection. Consistent with our in vitro data, we hypothesize that Vitamin A deficiency prevents the in vivo differentiation of allospecific Treg. We seek to prove this hypothesis in in vivo models of allograft tolerance whereby the differentiation and function of allospecific Treg can be critically investigated and quantified. We have identified multiple genetic models where RA signaling in T cells, CD4+ T cells and Foxp3+ T cells can be specifically manipulated in vivo to causally implicate RA-dependent T cell signaling and peripheral tolerance. 3) Regulation of RA synthesis within the regional LN and the immune privileged microenvironment. We propose that RA synthesis by hematopoietic cells in the immune privileged microenvironment controls the differentiation of Treg. As such we propose that hematopoietic cells within the graft microenvironment or regional LN controls Teff AETreg differentiation through RA synthesis in vivo, and causally implicate the production of RA by a specific cell type to the persistence of graft tolerance. We will also evaluate the factors (cytokines, chemokines, other) that regulate the expression of key enzymatic pathways that control RA production. Such studies will provide valuable insights into the use of RA agonists and antagonists in the management of immune related diseases.

Public Health Relevance

Numerous studies have demonstrated that Vitamin A supplementation reduces morbidity and mortality from infectious diseases through its rejuvenating impact on the immune system. This proposal will discover the underlying molecular, cellular and immunologic consequences of Vitamin A deficiency and repletion on the immune system in health and disease. This will provide a rationale basis for use of this natural medicine on the treatment of immune related disorders.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT005382-05
Application #
8540340
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Pontzer, Carol H
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$480,451
Indirect Cost
$179,982
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub et al. (2013) Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood 122:2125-34
Pino-Lagos, Karina; Guo, Yanxia; Brown, Chrysothemis et al. (2011) A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J Exp Med 208:1767-75
de Vries, Victor C; Pino-Lagos, Karina; Nowak, Elizabeth C et al. (2011) Mast cells condition dendritic cells to mediate allograft tolerance. Immunity 35:550-61