The subversion of treg-mediated transplantation tolerance by toll-like receptor signals / Paige Marie Porrett.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Porrett, Paige Marie.

Contributor:

Turka, Laurence A., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Allergy and Immunology.

Academic Dissertations as Topic.

Medical Subjects:

Allergy and Immunology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Physical Description:

xii, 116 pages : illustrations ; 29 cm

Production:

2008.

Summary:

Immune activation via Toll-like receptors (TLRs) has recently been identified as an important barrier to the induction of donor-specific transplantation tolerance, but the exact mechanisms underlying this barrier remain unclear. To better understand how TLR ligation interferes with the induction of donor-specific tolerance, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4+Foxp3+ regulatory T cells, and that TLR ligation prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that TLR ligands mediate these effects in the absence of IL-6, and that Th17 cells do not participate in the abrogation of tolerance by TLR ligands. Finally, in light of our observation that rapamycin induces CD4+Foxp3+ adaptive Treg conversion from alloreactive Foxp3-effector T cells, we investigated the role of these cells in the tolerance process and conclude that natural Tregs are the dominant Foxp3+ regulatory T cell subset that establishes immunoregulation in animals treated with costimulatory blockade and rapamycin. Altogether, these data suggest that TLR signals do not prevent prolonged graft acceptance by preventing alloantigen-specific adaptive Treg differentiation. Instead, graft destruction results from the ability of TLR ligands to promote Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4+Foxp3+ Tregs.

Notes:

Adviser: Laurence A. Turka.

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2008.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3346182