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Regulation of CD8+ T cell immunity by retinoic acid / by Yanxia Guo.

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Author	Guo, Yanxia.
Title	Regulation of CD8+ T cell immunity by retinoic acid / by Yanxia Guo.
Date	2013
Abstract	Studies have implicated the essential role of Vitamin A (VA) and its active metobolite, retinoic acid (RA) in both host defense and tolerance through manipulation of various immune cells, including T cells, B cells, macrophages and others. CD8⁺ T cells are a key component in protection against both cancer and infectious diseases. Therefore, we designed studies to understand the function of RA signaling in the development of CD8+ T cell immunity. Herein, it is shown for the first time that local RA production within the tumor microenvironment (TME) is increased up to 5-fold compared to naïve surrounding tissue, with a commensurate increase in RA signaling to regionally infiltrating tumor-reactive T cells. Conditional disruption of RA signaling in CD8⁺ T cells using a dominant negative Retinoic Acid Receptor [alpha] (dnRAR[alpha]) illustrated that RA signaling is required for tumor-specific CD8⁺ T cell expansion/accumulation and protective anti-tumor immunity. In-depth in vivo analysis of antigen-specific CD8⁺ T cell responses have revealed that early T cell expansion is independent of RA. However, late T cell expansion and clonal accumulation is profoundly suppressed in the absence of RA signaling. These studies established a novel function of RA essential for the survival of tumor-reactive CD8⁺ T cells within the TME. Our further studies dissected the intrinsic role of each of the RAR isotypes in the clonal expansion, differentiation and survival of pathogen-specific CD8⁺ T cells in vivo. The data show that RAR[alpha] is required for the expression of gut-homing receptors on CD8⁺ T cells and survival of CD8⁺ T cells in vitro. Furthermore, RAR[alpha] is essential for survival of CD8⁺ T cells in vivo following Listeria monocytogenenesis (LM) infection. In contrast RAR[beta] is indispensable for antigen-specific CD8⁺ T cell expansion during infection. The defective survival of RAR[alpha] deficient CD8⁺ T cells led to a deficiency in control of
Description	xx, 225 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Mary Jo Turk, James D. Gorham, Randolph J. Noelle, Daniel Mucida
College	Dartmouth Medical School. Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.965

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