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The Role of Lymphatic Endothelial Cells in T Cell Tolerance

Rouhani, Sherin
Format
Thesis/Dissertation; Online
Author
Rouhani, Sherin
Advisor
Engelhard, Victor
Abstract
The adaptive immune response can recognize a tremendous variety of antigens. Therefore, robust self-tolerance mechanisms are critical to prevent autoimmunity. Tolerance begins during T cell development in the thymus and continues in lymph nodes. Recently, we demonstrated that lymphatic endothelial cells (LEC) transcribe tyrosinase mRNA and present tyrosinase on MHC I molecules to CD8 T cells, inducing deletional tolerance of tyrosinase-reactive T cells. LEC express intermediate levels of MHC II molecules, suggesting they may play a role in CD4 T cell tolerance as well. Here, we demonstrate that LEC do not directly present epitopes from β-galactosidase or hemagglutinin on MHC II to CD4 T cells, although they do present epitopes from these antigens on MHC I to CD8 T cells. Instead, LEC transfer these antigens to dendritic cells, which induce CD4 T cell anergy. LEC express multiple components of the MHC II processing pathway, including invariant chain and cathepsin L, but do not express H2-M, suggesting that they are unable to load antigenic peptides onto MHC II molecules. MHC II is a ligand for the LAG-3 inhibitory pathway, and we demonstrate that deletional tolerance of β-galactosidase-specific CD8 T cells requires both the PD-1/PD-L1 and LAG-3/MHC II pathways. This suggests that a major role of MHC II molecules on LEC is to maintain CD8 T cell tolerance. We also examined whether LEC-induced tolerance is abrogated under inflammatory conditions. LEC express toll-like receptors 3 and 4, and in vivo ligation of these receptors leads to upregulation of PD-L1 but not CD70, CD80, CD86 or 4-1BBL. TLR3 ligation had no effect on tolerance induction by LEC. Surprisingly, however, treatment with an agonistic CD40 antibody led to the accumulation, rather than deletion, of tyrosinase specific T cells, and bone marrow chimeras demonstrated that this was due to the effects of CD40 on hematopoietic cells. We also investigated which APC immunogenically presents tyrosinase leading to autoimmune vitiligo, and found that CD8α+ or CD103+ cross-presenting dendritic cells are responsible for vitiligo induction in adults, but not in neonatal animals. Finally, we showed that inhibiting LEC-induced tolerance to tyrosinase by blocking the PD-1/PD-L1 pathway enhances melanoma immunotherapy.
Language
English
Published
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD (Doctor of Philosophy), 2014
Published Date
2014-09-29
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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