Date of Award

Spring 5-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Various thymic APC subsets have been invoked in deletional tolerance and Treg cell induction, but previous studies either assessed total T cell numbers or used TCR transgenic lines, obscuring roles that individual thymic APC subsets might serve for particular antigen-specific T cell populations. Utilizing T cell receptor sequencing, we found that medullary thymic epithelial cells (mTECs) and bone marrow-derived (BM) APCs delete or select unique conventional and Treg cell TCR repertoires, demonstrating distinct roles for these APCs. We show that BM APCs and mTECs each contribute to Aire-dependent T cell tolerance development, albeit through either cooperative or autologous antigen presentation respectively, and that cooperative antigen transfer is likely performed by thymic CD8+ DCs. Using our established TCR sequencing approach, In addition, we sought to understand CD8+ DC-mediated cooperative antigen presentation further. We quantified the extent of CD8+ DC-dependent Treg cell and negative selection and the proportion of this selection that is achieved through Aire-dependent cooperative antigen transfer. We also found that CD36 expression by CD8+ DCs facilitates Aire-dependent cooperative antigen transfer both in vivo and via TCR sequencing. Finally, we found that in the absence of thymic CD8+ DCs or CD36 expression; direct allo-tolerance fails to develop leading to catastrophic acute GVHD.

Language

English (en)

Chair and Committee

Chyi-Song Hsieh

Committee Members

Paul Allen, Brian Edelson, Takeshi Egawa, Kenneth Murphy,

Comments

Permanent URL: https://doi.org/10.7936/K75H7DJR

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