PMID- 33101265 OWN - NLM STAT- MEDLINE DCOM- 20210420 LR - 20231130 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - Cytomegalovirus-Mediated T Cell Receptor Repertoire Perturbation Is Present in Early Life. PG - 1587 LID - 10.3389/fimmu.2020.01587 [doi] LID - 1587 AB - Human cytomegalovirus (CMV) is a highly prevalent herpesvirus, particularly in sub-Saharan Africa, where it is endemic from infancy. The T cell response against CMV is important in keeping the virus in check, with CD8 T cells playing a major role in the control of CMV viraemia. Human leukocyte antigen (HLA) B(*)44:03-positive individuals raise a robust response against the NEGVKAAW (NW8) epitope, derived from the immediate-early-2 (IE-2) protein. We previously showed that the T cell receptor (TCR) repertoire raised against the NW8-HLA-B(*)44:03 complex was oligoclonal and characterised by superdominant clones, which were shared amongst unrelated individuals (i.e., "public"). Here, we address the question of how stable the CMV-specific TCR repertoire is over the course of infection, and whether substantial differences are evident in TCR repertoires in children, compared with adults. We present a longitudinal study of four HIV/CMV co-infected mother-child pairs, who in each case express HLA-B(*)44:03 and make responses to the NW8 epitope, and analyse their TCR repertoire over a period spanning more than 10 years. Using high-throughput sequencing, the paediatric CMV-specific repertoire was found to be highly diverse. In addition, paediatric repertoires were remarkably similar to adults, with public TCR responses being shared amongst children and adults alike. The CMV-specific repertoire in both adults and children displayed strong fluctuations in TCR clonality and repertoire architecture over time. Previously characterised superdominant clonotypes were readily identifiable in the children at high frequency, suggesting that the distortion of the CMV-specific repertoire is incurred as a direct result of CMV infection rather than a product of age-related "memory inflation." Early distortion of the TCR repertoire was particularly apparent in the case of the TCR-beta chain, where oligoclonality was low in children and positively correlated with age, a feature we did not observe for TCR-alpha. This discrepancy between TCR-alpha and -beta chain repertoire may reflect differential contribution to NW8 recognition. Altogether, the results of the present study provide insight into the formation of the TCR repertoire in early life and pave the way to better understanding of CD8 T cell responses to CMV at the molecular level. CI - Copyright (c) 2020 Attaf, Roider, Malik, Rius Rafael, Dolton, Predergast, Leslie, Ndung'u, Kloverpris, Sewell and Goulder. FAU - Attaf, Meriem AU - Attaf M AD - Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. AD - Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom. FAU - Roider, Julia AU - Roider J AD - Human Immunodeficiency Virus Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. AD - Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. AD - German Centre for Infection Research, Munich, Germany. AD - Department of Infectious Diseases, Ludwig-Maximilians-University, Munich, Germany. FAU - Malik, Amna AU - Malik A AD - Department of Paediatrics, University of Oxford, Oxford, United Kingdom. FAU - Rius Rafael, Cristina AU - Rius Rafael C AD - Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. AD - Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom. FAU - Dolton, Garry AU - Dolton G AD - Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. AD - Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom. FAU - Predergast, Andrew J AU - Predergast AJ AD - Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe. AD - Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom. AD - Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States. FAU - Leslie, Alasdair AU - Leslie A AD - Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. AD - Infection and Immunity, University College London, London, United Kingdom. FAU - Ndung'u, Thumbi AU - Ndung'u T AD - Human Immunodeficiency Virus Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. AD - Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. AD - Infection and Immunity, University College London, London, United Kingdom. AD - The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, United States. AD - Virology and Immunology, Max Planck Institute for Infection Biology, Berlin, Germany. FAU - Kloverpris, Henrik N AU - Kloverpris HN AD - Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. AD - Infection and Immunity, University College London, London, United Kingdom. FAU - Sewell, Andrew K AU - Sewell AK AD - Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. AD - Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom. FAU - Goulder, Philip J AU - Goulder PJ AD - Department of Paediatrics, University of Oxford, Oxford, United Kingdom. AD - The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, United States. LA - eng GR - R01 AI133673/AI/NIAID NIH HHS/United States GR - WT100327MA/WT_/Wellcome Trust/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - PG WT104748MA/WT_/Wellcome Trust/United Kingdom GR - 202485/Z/16/Z/WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200930 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, Viral) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA Antigens) RN - 0 (Peptides) RN - 0 (Receptors, Antigen, T-Cell) SB - IM EIN - Front Immunol. 2020 Dec 21;11:633633. PMID: 33408722 MH - Adolescent MH - Adult MH - Age Factors MH - Antigens, Viral/immunology MH - CD8-Positive T-Lymphocytes/immunology/metabolism MH - Child MH - Child, Preschool MH - Coinfection MH - Cytomegalovirus/*immunology MH - Cytomegalovirus Infections/*immunology/*metabolism/virology MH - Epitopes, T-Lymphocyte/chemistry/immunology MH - Female MH - HIV Infections/immunology/virology MH - HLA Antigens/immunology MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Infant MH - Leukocytes, Mononuclear/immunology/metabolism MH - Peptides/chemistry/immunology MH - Receptors, Antigen, T-Cell/genetics/*metabolism MH - T-Cell Antigen Receptor Specificity MH - T-Lymphocytes/*immunology/*metabolism MH - Viral Load MH - Young Adult PMC - PMC7554308 OTO - NOTNLM OT - HLA-B*44:03 OT - T cell receptor OT - T cell receptor repertoire OT - cytomegalovirus OT - memory inflation OT - paediatric repertoire OT - repertoire dynamics OT - superdominance EDAT- 2020/10/27 06:00 MHDA- 2021/04/21 06:00 PMCR- 2020/01/01 CRDT- 2020/10/26 05:22 PHST- 2020/03/30 00:00 [received] PHST- 2020/06/15 00:00 [accepted] PHST- 2020/10/26 05:22 [entrez] PHST- 2020/10/27 06:00 [pubmed] PHST- 2021/04/21 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.01587 [doi] PST - epublish SO - Front Immunol. 2020 Sep 30;11:1587. doi: 10.3389/fimmu.2020.01587. eCollection 2020.