Cytomegalovirus-Mediated T Cell Receptor Repertoire Perturbation Is Present in Early Life

Research output: Contribution to journalJournal articleResearchpeer-review

  • Meriem Attaf
  • Julia Roider
  • Amna Malik
  • Cristina Rius Rafael
  • Garry Dolton
  • Andrew J. Predergast
  • Alasdair Leslie
  • Thumbi Ndung'u
  • Kløverpris, Henrik Nyhus
  • Andrew K. Sewell
  • Philip J. Goulder

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-β chain, where oligoclonality was low in children and positively correlated with age, a feature we did not observe for TCR-α. This discrepancy between TCR-α and -β 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.

Original languageEnglish
Article number1587
JournalFrontiers in Immunology
Volume11
ISSN1664-3224
DOIs
Publication statusPublished - 2020
Externally publishedYes

Bibliographical note

Funding Information:
The study was conceived by AS and PG and funded by grants to AS and PG. MA, JR, AM, CR, and GD did the experimental work that was supervised by AS, HK, TN, and PG. The data were analysed by MA, JR, AL, HK, AS, and PG. The manuscript was written by MA, JR, AL, HK, TN, AS, and PG. All authors contributed to the article and approved the submitted version.

Publisher Copyright:
© Copyright © 2020 Attaf, Roider, Malik, Rius Rafael, Dolton, Predergast, Leslie, Ndung'u, Kløverpris, Sewell and Goulder.

    Research areas

  • cytomegalovirus, HLA-B44:03, memory inflation, paediatric repertoire, repertoire dynamics, superdominance, T cell receptor, T cell receptor repertoire

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