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.

Committee Chair

Chyi-Song Hsieh

Committee Members

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

Comments

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

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

Spring 5-15-2016

Language

English (en)

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