H. polygyrus infection mediates regulatory T cell function in the gut of mice.
T cells are crucial for maintaining homeostasis in the body. These cells come in many
varieties and serve different roles based on their location, induction, and protein
repertoire. The transcription factor Foxp3, marks an especially important group of
regulatory T cells that can further be divided based on their classification as CD4+ or
CD8+ and their ability to produce... read moreother factors such as the anti-inflammatory cytokine
IL-10. Regulatory T cells are especially needed in the gut where the resident immune
cells are continually exposed to a variety of antigens from both pathogenic and
non-pathogenic sources. A lack of regulation leads to uncontrolled inflammation and
colitis. The regulatory immune environment of the gut is enhanced following infection
with the intestinal parasite Heligmosomoides polygyrus (H. poly). In this thesis project
I have investigated four groups of regulatory T cells that reside in the gut and are
enhanced following infection with H. poly. Following infection and when exposed to the
helminth-induced cytokines TGF-β and IL-2, Foxp3+CD8+ T cells are maintained in
culture and Foxp3 expression is increased by two-fold. These findings coupled with
functional assays suggest that these unique regulatory T cells are regulators of
inflammation in the gut following infection with H. poly. Likewise, when Foxp3+ T cells
are divided into Foxp3+IL-10+ and Foxp3+IL-10- T cells, TGF-β and IL-2 also have
an effect on regulatory cell maintenance. Foxp3+IL-10+ T cells, which are essential for
preventing colitis, are preferentially maintained. In functional assays, H. poly
infection altered the ability of Foxp3+IL-10+ T cells to inhibit proliferation.
Molecular analysis of these Foxp3 subsets continues to reveal differences that may
reveal their specific roles during H. poly infection. Finally, despite the strict
requirement for gut homeostasis, I have shown that IL-10 can be inhibited by T cells in
the gut in a helminth-dependent manner. All of these findings together show a very
complex system of regulation that is reliant on T cells and further modified by
infection with H. poly. This system of regulators illustrates how the gut immune system
can prevent inflammation even in the constant presence of antigen. Having a better
understanding of how these regulatory pathways work and are enhanced following H. poly
infection is vital in the development of treatments for IBD in
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Immunology.
Advisors: Joel Weinstock, and Thereza Imanishi-Kari.
Committee: Alexander Poltorak, and Linden Hu.
Keyword: Immunology.read less