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Regulation of dendritic cell functions by human uterine epithelial cells: Implications for HIV-1 infection of the endometrium.

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Call No.	Ph.D. 2010
Author	Ochiel, Daniel Otieno.
Title	Regulation of dendritic cell functions by human uterine epithelial cells: Implications for HIV-1 infection of the endometrium.
Date	2010
Abstract	The human female reproductive tract (FRT) maintains a state of immune tolerance to spermatozoa and fetal allografts, while retaining the capacity to respond to a number of sexually transmitted infections (STIs) including human immunodeficiecy virus 1 (HIV-1). Emerging evidence indicates that epithelial cells that line the uterine lumen, the sentinel cells of this mucosal tissue, secrete a spectrum of immune mediators. These mediators orchestrate the cell-cell interactions that regulate immunity in the uterus, and determine its susceptibility to HIV-1 infection. To define the molecular and cellular mechanims that underlie immune responses in the uterus, the first hypothesis tested by this thesis is that specific soluble factors produced by uterine epithelial cells (UEC) modulate the differentiation and immune functions of dendritic cells (DC), the professional antigen presenting cells that link the innate and adaptive immune systems. Secondly, we hypothesized that UEC secretions alter the infectivity of DC to HIV-1 infection by regulating the expression of surface receptors required for virus entry. We show that UEC secretions modulate the differentiation of DC from monocyte precursors, inducing the development of DC with tolerogenic properties. In addition, we show UEC secretions to significantly enhance the expression of the HIV-1 co-receptor CXCR4 while concomitantly decreasing the expression of DC-SIGN, a molecule utilized by DC to capture and transfer HIV-1. The inhibitory effect of UEC secretions on DC-SIGN expression was partly dependent on the biologically active Transforming Growth Factor-beta (TGF-?) secreted basolaterally by polarized UEC. As part of these studies, we found that UEC secretions inhibited trans infection of DC by HIV-1 expressing env genes from transmitted/founder HIV-1. In contrast, HIV-1 expressing env genes from transmitted/founder virions were relatively refractory to TGF-?1 inhibition of trans infection by DC. The recognition that UEC secretions contain inhibitors that interfere with DC-mediated trans infection of transmitted/founder HIV-1 in the uterus offers new insight into novel strategies to block sexual transmission of HIV-1 transmitted/founder viruses.
Description	xiii, 155 leaves : ill. (some col.) ; 28 cm.
Format	application/pdf
Advisor	Wira, Charles R., Guyre, Paul M., Henderson, Leslie P., Green, William R., Gupta, Phalguni
Subject	Dendritic cells. Uterus -- Immunology. Epithelium -- Immunology. Epithelial cells. HIV infections -- Molecular aspects.
College	Dartmouth Medical School. Department of Physiology.
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.398

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Regulation of Dendritic Cell Functions by Human Uterine Epithelial Cells: Implications for HIV-1 Infection of the Endometrium A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in Physiology by Daniel Otieno Ochiel DARTMOUTH COLLEGE Hanover, New Hampshire January, 2010 Examining Committee: _______________________ Charles R. Wira, Ph.D (Chair) ________________________ Paul M. Guyre, Ph.D ________________________ Leslie P. Henderson, Ph.D ______________________ William R. Green, Ph.D ______________________ Phalguni Gupta, Ph.D ________________________________________ Brian W. Pogue, Ph.D., Dean of Graduate Studies

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