Date of Award

5-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbial Pathogenesis, Immunology, and Inflammation

Research Advisor

Terrence L. Geiger, M.D., Ph.D.

Committee

Hongbo Chi, Ph.D. Elizabeth A. Fitzpatrick, Ph.D. David Nelson, Ph.D. Dario Vignali, Ph.D.

Abstract

Regulatory T-cells (Treg) play an important role in maintaining immune tolerance to self-antigens and in suppressing excessive immune responses in the host. The source, specificity, and plasticity of the forkhead box transcription factor 3 (Foxp3+) Treg and conventional T (Tconv) cell populations active at sites of autoimmune pathology are not well characterized. To evaluate this, we combined global repertoire analyses and functional assessments of isolated T-cell receptors (TCR) from TCRa retrogenic mice with autoimmune encephalomyelitis (EAE). Treg and Tconv cell TCR repertoires were distinct, and autoantigen-specific Treg and Tconv cells were enriched in diseased tissue. Autoantigen sensitivity and fine specificity of these cells intersected, implying that differences in responsiveness were not responsible for lineage specification. Notably, autoreactive Treg and Tconv cells could be fully distinguished by an acidic versus aliphatic variation at a single TCR CDR3 residue. Our results imply that ontogenically distinct Treg and Tconv cell repertoires with convergent specificities for autoantigen respond during autoimmunity and argue limited plasticity between Treg and Tconv cells during autoimmune inflammation.

DOI

10.21007/etd.cghs.2010.0188

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