Single-cell approach to influenza-specific CD8+ T cell receptor repertoires across different age groups, tissues, and following influenza virus infection

Sneha Sant, Ludivine Grzelak, Zhongfang Wang, Angela Pizzolla, Marios Koutsakos, Jane Crowe, Thomas Loudovaris, Stuart I. Mannering, Glen P. Westall, Linda M. Wakim, Jamie Rossjohn, Stephanie Gras, Michael Richards, Jianqing Xu, Paul G. Thomas, Liyen Loh, Thi H.O. Nguyen, Katherine Kedzierska

Research output: Contribution to journalArticleResearchpeer-review

Abstract

CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158-66 (A2+M158). We dissected memory TCR repertoires directed toward A2+M158 CD8+ T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8+ T cell repertoires to A2+M158 CD8+ TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first ex vivo comparative analysis of paired antigen-specific TCR-α/β clonotypes across different tissues and peripheral blood across different age groups. We show that human A2+M158 CD8+ T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2+M158 TCRαβ repertoires reflect A2+M158 TCRαβ clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2+M158 TCRαβ repertoires displayed distinct features only in elderly adults, with large private TCRαβ clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRαβ repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRαβ signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies.

Original languageEnglish
Article number1453
Number of pages18
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 27 Jun 2018

Keywords

  • Aging
  • CD8 T cells
  • Human T lymphocytes
  • Influenza A virus
  • T cell receptor repertoire
  • Tissues

Cite this

Sant, Sneha ; Grzelak, Ludivine ; Wang, Zhongfang ; Pizzolla, Angela ; Koutsakos, Marios ; Crowe, Jane ; Loudovaris, Thomas ; Mannering, Stuart I. ; Westall, Glen P. ; Wakim, Linda M. ; Rossjohn, Jamie ; Gras, Stephanie ; Richards, Michael ; Xu, Jianqing ; Thomas, Paul G. ; Loh, Liyen ; Nguyen, Thi H.O. ; Kedzierska, Katherine. / Single-cell approach to influenza-specific CD8+ T cell receptor repertoires across different age groups, tissues, and following influenza virus infection. In: Frontiers in Immunology. 2018 ; Vol. 9.
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title = "Single-cell approach to influenza-specific CD8+ T cell receptor repertoires across different age groups, tissues, and following influenza virus infection",
abstract = "CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158-66 (A2+M158). We dissected memory TCR repertoires directed toward A2+M158 CD8+ T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8+ T cell repertoires to A2+M158 CD8+ TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first ex vivo comparative analysis of paired antigen-specific TCR-α/β clonotypes across different tissues and peripheral blood across different age groups. We show that human A2+M158 CD8+ T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2+M158 TCRαβ repertoires reflect A2+M158 TCRαβ clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2+M158 TCRαβ repertoires displayed distinct features only in elderly adults, with large private TCRαβ clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRαβ repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRαβ signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies.",
keywords = "Aging, CD8 T cells, Human T lymphocytes, Influenza A virus, T cell receptor repertoire, Tissues",
author = "Sneha Sant and Ludivine Grzelak and Zhongfang Wang and Angela Pizzolla and Marios Koutsakos and Jane Crowe and Thomas Loudovaris and Mannering, {Stuart I.} and Westall, {Glen P.} and Wakim, {Linda M.} and Jamie Rossjohn and Stephanie Gras and Michael Richards and Jianqing Xu and Thomas, {Paul G.} and Liyen Loh and Nguyen, {Thi H.O.} and Katherine Kedzierska",
year = "2018",
month = "6",
day = "27",
doi = "10.3389/fimmu.2018.01453",
language = "English",
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journal = "Frontiers in Immunology",
issn = "1664-3224",
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Sant, S, Grzelak, L, Wang, Z, Pizzolla, A, Koutsakos, M, Crowe, J, Loudovaris, T, Mannering, SI, Westall, GP, Wakim, LM, Rossjohn, J, Gras, S, Richards, M, Xu, J, Thomas, PG, Loh, L, Nguyen, THO & Kedzierska, K 2018, 'Single-cell approach to influenza-specific CD8+ T cell receptor repertoires across different age groups, tissues, and following influenza virus infection' Frontiers in Immunology, vol. 9, 1453. https://doi.org/10.3389/fimmu.2018.01453

Single-cell approach to influenza-specific CD8+ T cell receptor repertoires across different age groups, tissues, and following influenza virus infection. / Sant, Sneha; Grzelak, Ludivine; Wang, Zhongfang; Pizzolla, Angela; Koutsakos, Marios; Crowe, Jane; Loudovaris, Thomas; Mannering, Stuart I.; Westall, Glen P.; Wakim, Linda M.; Rossjohn, Jamie; Gras, Stephanie; Richards, Michael; Xu, Jianqing; Thomas, Paul G.; Loh, Liyen; Nguyen, Thi H.O.; Kedzierska, Katherine.

In: Frontiers in Immunology, Vol. 9, 1453, 27.06.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Single-cell approach to influenza-specific CD8+ T cell receptor repertoires across different age groups, tissues, and following influenza virus infection

AU - Sant, Sneha

AU - Grzelak, Ludivine

AU - Wang, Zhongfang

AU - Pizzolla, Angela

AU - Koutsakos, Marios

AU - Crowe, Jane

AU - Loudovaris, Thomas

AU - Mannering, Stuart I.

AU - Westall, Glen P.

AU - Wakim, Linda M.

AU - Rossjohn, Jamie

AU - Gras, Stephanie

AU - Richards, Michael

AU - Xu, Jianqing

AU - Thomas, Paul G.

AU - Loh, Liyen

AU - Nguyen, Thi H.O.

AU - Kedzierska, Katherine

PY - 2018/6/27

Y1 - 2018/6/27

N2 - CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158-66 (A2+M158). We dissected memory TCR repertoires directed toward A2+M158 CD8+ T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8+ T cell repertoires to A2+M158 CD8+ TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first ex vivo comparative analysis of paired antigen-specific TCR-α/β clonotypes across different tissues and peripheral blood across different age groups. We show that human A2+M158 CD8+ T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2+M158 TCRαβ repertoires reflect A2+M158 TCRαβ clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2+M158 TCRαβ repertoires displayed distinct features only in elderly adults, with large private TCRαβ clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRαβ repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRαβ signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies.

AB - CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158-66 (A2+M158). We dissected memory TCR repertoires directed toward A2+M158 CD8+ T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8+ T cell repertoires to A2+M158 CD8+ TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first ex vivo comparative analysis of paired antigen-specific TCR-α/β clonotypes across different tissues and peripheral blood across different age groups. We show that human A2+M158 CD8+ T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2+M158 TCRαβ repertoires reflect A2+M158 TCRαβ clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2+M158 TCRαβ repertoires displayed distinct features only in elderly adults, with large private TCRαβ clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRαβ repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRαβ signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies.

KW - Aging

KW - CD8 T cells

KW - Human T lymphocytes

KW - Influenza A virus

KW - T cell receptor repertoire

KW - Tissues

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JO - Frontiers in Immunology

JF - Frontiers in Immunology

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