Advisor(s)
Harry W Schroeder
Committee Member(s)
Peter Burrows
Lesley Smythies
Laura Timares
Allan Zajac
Document Type
Dissertation
Date of Award
2018
Abstract
T cell receptor (TCR) is a surface glycoprotein found on T cells that recognizes peptides bound to major histocompatibility complex (MHC) molecules (pMHC). Each TCR is a heterodimer consisting of an alpha (α) and a beta (β) chain that are created by rearrangements of variable (V), diversity (D), and joining (J) gene segments in the thymus. The most diverse component of the β chain is its third complementarity determining region, or CDR-B3. CDR-B3 is created de novo for each individual T cell by VDJ rearrangement and together with its TCRα partner, CDR-A3, creates the center of the TCR pMHC binding site. The sequences of D gene segments are highly conserved, with humans, mice, and trout having identical Dβ1 gene sequence. It is a central tenet of natural selection that the more conserved the gene sequence, the more likely the encoded protein has a critical functional role. Therefore, the goal of this study was to investigate the role of the conservation of Dβ in determining CDR-B3 content, as well as the fate and function of T cells. To do this, gene targeting was performed on mice that only possessed a single DβJβ gene segment, altering the remaining Dβ gene segment by an immunoglobulin DH with reading frames coding for tyrosine or hydrophobic amino acids, or by a novel Dβ sequence that codes for charged amino acids. Previous studies on immunoglobulin CDR-H3 (the B cell homologue to TCR) showed that similar alterations to the DH gene segment drastically changed the B cell repertoire, had deleterious effects on B cell numbers, diminished antibody production, and altered epitope recognition. We found that these changes to the Db gene segment elicited the same effects in T cells. Mutant Dβ mice had a drastically altered repertoire, were highly selected against in the periphery, and had reduced recognition of immunodominant epitopes post-vaccination. This study supports the view that the sequences of the D gene segments have undergone natural selection to counter the effect of random N nucleotide addition by constraining the core of the antigen binding site repertoire to favor the presence of specific amino acids at specific positions.
ProQuest Publication Number
ISBN
978-0-438-34387-0
Recommended Citation
Levinson, Michael Steven, "Conserved Tcr Dβ Biases Cdr-B3 Content And Alters T Cell Development And Function" (2018). All ETDs from UAB. 2257.
https://digitalcommons.library.uab.edu/etd-collection/2257
Comments
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