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"In vivo analysis of innate immune responses supporting the initiation of T helper 2 cell differentiation during parasitic helminth infection"

by
Cristina T. Rozo
Interdisciplinary Biomedical Sciences Program
B.A. 2001, University of Delaware



Thesis Advisor: William C. Gause, Ph.D.
Professor
Department of Medicine

Monday, October 25, 2010
MSB B-610, 2:00 p.m.


Abstract

The cell populations and molecules involved in triggering the development of Th2 cells remain uncertain. Using an infectious parasitic animal model, Nippostrongylus brasiliensis, which induces a potent and polarized in vivo Th2-type response, our previous studies showed that in vivo Th2 cell differentiation occurs in the absence of IL-4 production by non-T cells as early as 2-3 days after intracutaneous N. brasiliensis inoculation. To examine which innate immune cell populations contribute to the in vivo development of IL-4 producing T cells in the lymph node, antigen presenting cells were identified with DQ-OVA, which fluoresces while processing antigen. Our studies suggest that under Th2 conditions in the draining lymph node, interstitial DCs present antigen 24 hours following intracutaneous N. brasiliensis inoculation and that DX5+, FcR1+ basophils accumulate as early as 24 hours after immunization, but do not present antigen. While in vivo depletion of basophils by FcR1 antibody treatment reduced Th2 cytokine gene expression, it was not sufficient to block the initiation of the Th2-type response.
Previous studies suggested that thymic stromal lymphopoietin (TSLP) may stimulate DCs and accessory cells to induce the development of the Th2-type response. Both mucosal and non-mucosal immune responses were assessed at different times during the course of the primary immune response in TSLPR-/- mice inoculated with N. brasiliensis. It was determined that TSLP is differentially required for Th2 cell differentiation depending on the particular in vivo immune microenvironment, with the lung being particularly dependent on TSLP interactions. These studies begin to characterize the milieu where Th2 cell differentiation first occurs in response to N. brasiliensis. They indicate that the dominant antigen presenting cell appears similar in both Th1 and Th2-type responses; instead distinct accessory cells and factors may play the predominant role in driving the development of Th2 cell polarization.


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