Immunology and Microbiology
First Thesis Advisor
T cell, TCR, MHC, Peptide, Treg, T cell receptor, T Regulatory Cell, Alloreactivity, Immune Response
T cells use their highly variable T cell receptor (TCR) to engage major histocompatibility molecules (MHC) presenting peptides on the surface of antigen presenting cells during an immune response. The TCR repertoire of developing T cells is shaped by thymic selection, resulting in a self-tolerant and foreign peptide specific naïve T cell population. However, naive T cells are alloreactive and generate immune responses towards foreign MHC alleles in clinical settings involving transplantation. While T cell immune responses towards foreign pathogens are peptide specific, the overall specificity of allo-responses is still debated.
Under normal circumstances, immune system homeostasis and self-tolerance is maintained by specialized natural T regulatory cells (nTregs) that develop in the thymus. nTregs respond to self-peptide MHC they encountered in peripheral tissues with immune-suppressive activities. However, the identify of self-peptides that stimulate nTregs, specificity towards these self-peptides, and the method nTreg TCRs engage self-peptide MHC molecules is not clear.
Here, we built a library of defined MHC-linked self-peptides eluted from the I-Ab MHC molecule to screen alloreactive T cells and self-reactive nTregs for activating self-peptides. We used this library to show that negative selection shapes the TCR repertoire’s specificity to self-peptides. We also provide evidence that alloreactive T cells have degenerate self and foreign peptide recognition if the foreign MHC allele is largely different from the host’s MHC allele. Finally, we identified a self-peptide that activates an nTreg, and present protein crystal structures that reveal its TCR engages self and foreign peptide MHC complexes via fairly conventional mechanisms.
Duke, BR. Investigating the Peptide-MHC Specificity of Alloreactive T Cells and Natural T Regulatory Cells Using a Self-peptide Display Library. (2017). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 942. DOI: 10.13028/M22T1D. https://escholarship.umassmed.edu/gsbs_diss/942
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Available for download on Saturday, January 05, 2019