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"Toward a Better Understanding of Human CD4+ Treg Subsets:
A Study of Diverse Surface Markers, Functions, and Mechanisms"

by
Jessica Magid-Bernstein
MD/Ph.D. Program
B.A. 2006, Haverford College



Thesis Advisor: Christine Rohowsky-Kochan, Ph.D.
Professor
Department of Neurology & Neurosciences

Tuesday, April 30, 2013
10:00 A.M., G-1196, Cancer Center G Level Conference Room


Abstract

T regulatory (Treg) cells are a population of suppressive CD4+ T cells that downregulate inflammatory and autoimmune responses. Although high expression of the interleukin (IL)-2 receptor CD25 and the transcription factor Foxp3 are the canonical human Treg markers, upregulation of CD25 upon activation of CD4+ T cells and the fact that Foxp3 is expressed intracellularly make these markers less than ideal for Treg cell isolation. Additionally, research has indicated that functionally diverse Treg subsets exist and method and strength of activation play an important role in Treg function.
In this study, we investigated expression of the surface markers CD27, CD127, and CD39 on human Treg cells and characterized the function of CD27+CD127− and CD39+ Treg subsets. While CD4+CD25hiCD27+CD127− Treg cells suppress T effector (Teff) cell proliferation and interferon (IFN)-γ production following CD3/CD28 crosslinking, CD4+CD25hiCD39+ Treg cells are only suppressive when activated with αCD3 and irradiated allogeneic antigen presenting cells (APCs). Additionally, CD4+CD25hiCD39+ Treg cells suppress Teff cell IL-17 production in addition to proliferation and IFN-γ production, while CD4+CD25hiCD39− T cells only inhibit IFN-γ production. Upon investigating the mechanism by which CD4+CD25hiCD39+ Treg cells function, we determined that they did nibble surface membrane from APCs, but not more readily than CD4+CD25hiCD39− T cells, production of the inhibitory cytokines IL-10 and IL-35 did not correlate with suppression, and inhibition of adenosine production and binding did not reverse their suppressive ability. However, these cells did upregulate T helper 17 (Th17) cell the specific surface markers CCR6 and IL-23R upon activation, phosphorylation of the Th17-specific transcription factor signal transducer and activator of transcription-3 (STAT3) was greater in suppressive cultures, and inhibition of STAT3 activation partially reversed IL-17 suppression by these cells.
We also examined the requirement of IL-2 signaling for IL-17 production by CD4+ T cells. Our preliminary data indicates that signaling through CD25 is necessary for IL-17 production by na´ve CD4+ T cells, and results in downstream activation of the Th17-specific transcription factors STAT3 and T cell-expressed retinoic acid-related orphan receptor gamma (RORγt). As many autoimmune conditions exhibit alterations in specific T cell subsets, identification of subset-specific Treg cells, as well as the function of these Treg cells and their target T helper cell populations, is important for both understanding disease pathogenesis and developing effective treatments.


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