Advisory Committee Chair
Kohtaro Fujihashi
Advisory Committee Members
Peter D Burrows
Robinna G Lorenz
Suzanne M Michalek
Casey T Weaver
Document Type
Dissertation
Date of Award
2011
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Oral tolerance, defined as the immunologic state of systemic and mucosal unresponsiveness to an antigen, is an essential function of the mucosal immune system. Although antigen presentation has been found to play an important role in oral tolerance, T cells are known to be the effector immune cells that perpetrate this state. Recent studies found that antigen-specific T regulatory (Treg) cells are important in the induction and maintenance of oral tolerance. The extrathymic development of these Tregs depends on the presence of TGF-ß1 during the differentiation process. However, it has also been shown that oral tolerance could be induced in TGF-ß1 knockout mice. Given this contradicting information, we sought to further the understanding of the role of TGF-ß1 in high- and low-dose oral tolerance induction by focusing on the expression and function of TGFßRII, the signaling component of the oligomeric TGFß receptor complex, on CD4+ T cells of the systemic (spleen) and relevant mucosal [Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and small intestinal lamina propria (iLP)] immune tissues. We hypothesized that TGFßRII on CD4+ T cells is required for both low- and high-dose oral tolerance induction and therefore focused on the role the expression of this receptor by CD4+ T cells plays at early time points after exposure to the tolerogenic dose(s) of anti-gen. We found that the expression of TGFßRII by CD4+ T cells is upregulated at the site of antigen uptake -the PPs- soon after exposure to the tolerizing dose of antigen. Further, we showed that these cells diminish in the PPs and increase in the MLNs and iLP soon after re-exposure to the antigen in the presence of mucosal adjuvant. Also, by employing the CD4 dominant negative TGFßRII transgenic mouse model in which TGFßRII signaling in CD4+ T cells has been abrogated, we found that the proper function of TGFßRII is required for the induction of oral tolerance. Further analysis is necessary to tease out the exact function of these PP TGFßRII+ CD4+ T cells in the induction of oral tolerance.
Recommended Citation
Gilbert, Rebekah Sims, "The Role of TGF-ß Receptors in the Induction of Mucosal Tolerance" (2011). All ETDs from UAB. 1742.
https://digitalcommons.library.uab.edu/etd-collection/1742