T-cell receptor diversity of various antigen-specific T cells
Tjoa, Benjamin Alan
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Permalink
https://hdl.handle.net/2142/20614
Description
Title
T-cell receptor diversity of various antigen-specific T cells
Author(s)
Tjoa, Benjamin Alan
Issue Date
1994
Doctoral Committee Chair(s)
Kranz, David M.
Department of Study
Biochemistry
Discipline
Biochemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Chemistry, Biochemistry
Health Sciences, Immunology
Language
eng
Abstract
T cells recognize foreign antigen through a heterodimeric $\alpha\beta$ T-cell receptor (TCR). The TCR ligand is a peptide bound to a membrane-bound protein coded by the major histocompatibility complex (MHC) locus. Like immunoglobulins, the TCR repertoire is diverse because both the $\alpha$ and $\beta$ chains are coded by multiple genes that undergo rearrangement. The general goal of this study was to determine the diversity of TCRs from specific T cell populations, including T cells that are reactive with multiple ligands and TCRs that are reactive with a single peptide/MHC protein complex.
"The first part of this thesis describes the analysis of TCR structures used by T cells that mediate rejection in tissue transplantations. These T cells recognize foreign MHC proteins and because MHC proteins can each bind a variety of endogenous peptides, the T cells recognize multiple ligands (i.e., different peptide/MHC complexes). To generate T cells involved in transplant rejection, mice were injected at least two times (hyperimmunized) with cells that bear foreign MHC proteins and the ""transplant-reactive"" T cells were further enriched in culture. Transcripts of the $\alpha$-chains from these T cells were amplified using the polymerase chain reaction and sequenced. Results from this study showed that: (1) unlike immunoglobulin genes, somatic mutations did not occur in TCR genes from ""hyperimmune"" animals and (2) TCR transcripts from ""hyperimmune"" T cells specific for foreign MHC were diverse in sequence. However, after a long period ($>$40 days) in culture, ""dominant"" clones expressing particular TCR structures were found. If the long-term ""hyperimmune"" culture is indicative of the repertoire of cells that mediate transplant rejection, then such predominant TCR structures could serve as targets for specific suppression of transplant rejection."
The second part of this thesis describes the sequence analysis of TCR that are specific for a single peptide/MHC protein complex. The peptide involved in this study, p2Ca, is a ubiquitously expressed self-peptide that binds to an MHC protein called L$\sp{\rm d}$. Results showed that: (1) T cells that are specific for the p2Ca/L$\sp{\rm d}$ complex can be readily generated in vitro and (2) the T cells express a diverse TCR repertoire, although restrictions in the use of V$\beta$ and J$\beta$ regions were observed. The predominant use of particular V$\beta$ and J$\beta$ regions are discussed in the context of a model for the interaction between the $\alpha\beta$ TCR and the p2Ca/L$\sp{\rm d}$ complex. These findings are also discussed with regard to the potential for targeting autoimmune T cells and for peptide-based therapies that involve T-cell mediated tumor rejection.
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