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The Effect of MHC Heterozygosity on ...

Brown, Alexander Joseph,

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The Effect of MHC Heterozygosity on T Cell Receptor Diversity /

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Effect of MHC Heterozygosity on T Cell Receptor Diversity // Alexander Joseph Brown.
Author:	Brown, Alexander Joseph,
Description:	1 electronic resource (342 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
Contained By:	Dissertations Abstracts International85-11B.
Subject:	Immunology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30993218
ISBN:	9798382742489

The Effect of MHC Heterozygosity on T Cell Receptor Diversity /
Brown, Alexander Joseph,

The Effect of MHC Heterozygosity on T Cell Receptor Diversity /Alexander Joseph Brown. - 1 electronic resource (342 pages)

Source: Dissertations Abstracts International, Volume: 85-11, Section: B.

V(D)J genes of αβ T cell receptors (TCRs) recombine, yielding billions of TCRα+TCRβ combinations for interactions with self and foreign MHC/peptide ligands. Diverse MHC alleles present a broader array of foreign peptides to T cells, hindering escape of invading organisms from host immunity. MHC and T cell diversity are vital for species fitness and are linked to the development and protection from various autoimmune diseases. Despite extensive studies on MHC peptide specificity, little attention has been given to the impact of MHC on the expressed T cell receptor repertoire, particularly in MHC heterozygotes. Understanding the causal link between MHC alleles and TCR repertoire is a long-standing question that could guide personalized vaccine development, autoimmune monitoring, and prediction of responses to various therapeutic treatments.In this thesis, I explore the effect of MHC class I and MHC class II heterozygosity on the T cell receptor repertoire. I describe the effect on the TCR repertoire in an MHC class II heterozygous protective model of autoimmune diabetes and, primarily, mice I developed with a restricted TCR repertoire and the effect MHC homozygosity, MHC heterozygosity, MHC hemizygosity and MHC chimerism, on the selected TCRs of naive CD4+ and naive CD8+ T cells.The primary finding of this work is MHC heterozygotes can contain fairly large numbers of holes in their TCR VDJ sequences. This is to say, the T cell repertoire of some MHC heterozygotes is less than the sum of its parts. This work also dissects the mechanism of why these repertoire holes appear and highlights the dramatic effect thymic negative selection plays in determining the fate of the T cell repertoire in MHC heterozygotes. These results provide quantifiable evidence that an evolutionary consequence of increased MHC diversity is a reduction in the T cell receptor repertoire which in turn could limit the ability to mount effective T cell responses. Thus, it appears evolution has favored a balance between MHC allelic copy number and T cell receptor repertoire size to optimize immune responses.

English

ISBN: 9798382742489Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

T cells

The Effect of MHC Heterozygosity on T Cell Receptor Diversity /
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500 $a Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
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520 $a V(D)J genes of αβ T cell receptors (TCRs) recombine, yielding billions of TCRα+TCRβ combinations for interactions with self and foreign MHC/peptide ligands. Diverse MHC alleles present a broader array of foreign peptides to T cells, hindering escape of invading organisms from host immunity. MHC and T cell diversity are vital for species fitness and are linked to the development and protection from various autoimmune diseases. Despite extensive studies on MHC peptide specificity, little attention has been given to the impact of MHC on the expressed T cell receptor repertoire, particularly in MHC heterozygotes. Understanding the causal link between MHC alleles and TCR repertoire is a long-standing question that could guide personalized vaccine development, autoimmune monitoring, and prediction of responses to various therapeutic treatments.In this thesis, I explore the effect of MHC class I and MHC class II heterozygosity on the T cell receptor repertoire. I describe the effect on the TCR repertoire in an MHC class II heterozygous protective model of autoimmune diabetes and, primarily, mice I developed with a restricted TCR repertoire and the effect MHC homozygosity, MHC heterozygosity, MHC hemizygosity and MHC chimerism, on the selected TCRs of naive CD4+ and naive CD8+ T cells.The primary finding of this work is MHC heterozygotes can contain fairly large numbers of holes in their TCR VDJ sequences. This is to say, the T cell repertoire of some MHC heterozygotes is less than the sum of its parts. This work also dissects the mechanism of why these repertoire holes appear and highlights the dramatic effect thymic negative selection plays in determining the fate of the T cell repertoire in MHC heterozygotes. These results provide quantifiable evidence that an evolutionary consequence of increased MHC diversity is a reduction in the T cell receptor repertoire which in turn could limit the ability to mount effective T cell responses. Thus, it appears evolution has favored a balance between MHC allelic copy number and T cell receptor repertoire size to optimize immune responses.
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650 4 $a Bioinformatics. $3 553671
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653 $a T cells
653 $a Clonal selection
653 $a Immune evolution
653 $a Heterozygosity
653 $a T cell receptors
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