Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development

Enrichment for tyrosine in immunoglobulin CDR-H3 is due in large part to natural selection of germline immunoglobulin D(H) sequence. We have previously shown that when D(H) sequence is modified to reduce the contribution of tyrosine codons, epitope recognition is altered and B cell development, anti...

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Autores principales: Levinson, Michael, Khass, Mohamed, Burrows, Peter D., Schroeder, Harry W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550431/
https://www.ncbi.nlm.nih.gov/pubmed/33133088
http://dx.doi.org/10.3389/fimmu.2020.573413
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author Levinson, Michael
Khass, Mohamed
Burrows, Peter D.
Schroeder, Harry W.
author_facet Levinson, Michael
Khass, Mohamed
Burrows, Peter D.
Schroeder, Harry W.
author_sort Levinson, Michael
collection PubMed
description Enrichment for tyrosine in immunoglobulin CDR-H3 is due in large part to natural selection of germline immunoglobulin D(H) sequence. We have previously shown that when D(H) sequence is modified to reduce the contribution of tyrosine codons, epitope recognition is altered and B cell development, antibody production, autoantibody production, and morbidity and mortality following pathogen challenge are adversely affected. TCRβ diversity (Dβ) gene segment sequences are even more highly conserved than D(H), with trout Dβ1 identical to human and mouse Dβ1. We hypothesized that natural selection of Dβ sequence also shapes CDR-B3 diversity and influences T cell development and T cell function. To test this, we used a mouse strain that lacked Dβ2 and contained a novel Dβ1 allele (DβYTL) that replaces Dβ1 with an immunoglobulin D(H), DSP2.3. Unlike Dβ1, wherein glycine predominates in all three reading frames (RFs), in DSP2.3 there is enrichment for tyrosine in RF1, threonine in RF2, and leucine in RF3. Mature T cells using DβYTL expressed TCRs enriched at particular CDR-B3 positions for tyrosine but depleted of leucine. Changing Dβ sequence altered thymocyte and peripheral T cell numbers and the T cell response to an ovalbumin immunodominant epitope. The differences in tyrosine content might explain, at least in part, why TCRs are more polyspecific and of lower affinity for their cognate antigens than their immunoglobulin counterparts.
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spelling pubmed-75504312020-10-29 Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development Levinson, Michael Khass, Mohamed Burrows, Peter D. Schroeder, Harry W. Front Immunol Immunology Enrichment for tyrosine in immunoglobulin CDR-H3 is due in large part to natural selection of germline immunoglobulin D(H) sequence. We have previously shown that when D(H) sequence is modified to reduce the contribution of tyrosine codons, epitope recognition is altered and B cell development, antibody production, autoantibody production, and morbidity and mortality following pathogen challenge are adversely affected. TCRβ diversity (Dβ) gene segment sequences are even more highly conserved than D(H), with trout Dβ1 identical to human and mouse Dβ1. We hypothesized that natural selection of Dβ sequence also shapes CDR-B3 diversity and influences T cell development and T cell function. To test this, we used a mouse strain that lacked Dβ2 and contained a novel Dβ1 allele (DβYTL) that replaces Dβ1 with an immunoglobulin D(H), DSP2.3. Unlike Dβ1, wherein glycine predominates in all three reading frames (RFs), in DSP2.3 there is enrichment for tyrosine in RF1, threonine in RF2, and leucine in RF3. Mature T cells using DβYTL expressed TCRs enriched at particular CDR-B3 positions for tyrosine but depleted of leucine. Changing Dβ sequence altered thymocyte and peripheral T cell numbers and the T cell response to an ovalbumin immunodominant epitope. The differences in tyrosine content might explain, at least in part, why TCRs are more polyspecific and of lower affinity for their cognate antigens than their immunoglobulin counterparts. Frontiers Media S.A. 2020-09-29 /pmc/articles/PMC7550431/ /pubmed/33133088 http://dx.doi.org/10.3389/fimmu.2020.573413 Text en Copyright © 2020 Levinson, Khass, Burrows and Schroeder. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Levinson, Michael
Khass, Mohamed
Burrows, Peter D.
Schroeder, Harry W.
Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development
title Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development
title_full Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development
title_fullStr Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development
title_full_unstemmed Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development
title_short Replacement of TCR Dβ With Immunoglobulin D(H) DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development
title_sort replacement of tcr dβ with immunoglobulin d(h) dsp2.3 imposes a tyrosine-enriched tcr repertoire and adversely affects t cell development
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550431/
https://www.ncbi.nlm.nih.gov/pubmed/33133088
http://dx.doi.org/10.3389/fimmu.2020.573413
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