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Background <p>Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latency and becomes increasingly prevalent with age. To systematically delineate CMV-associated immune remodeling at single-cell resolution, we analysed six human cohorts (including two newly established cohorts) using single-cell RNA sequencing, T cell receptor (TCR) sequencing, and flow cytometry.</p> Results <p>We identified novel CMV-associated changes in cell frequencies, including increases in GZMK⁺ CD8⁺ T cells and atypical B cells, and a reduction in CD56dim NK cells, in addition to the canonical expansion of CD4⁺/CD8⁺ TEMRA and adaptive NK cells. Longitudinal profiling of an individual who seroconverted revealed rapid CMV-driven shifts in circulating immune cell frequencies. Leveraging a recently published CMV-specific TCRβ database, combined with predictive modeling (CMVerify), we identified novel CMV-specific clonal expansions that were reproduced across two independent cohorts. In the CD8⁺ lineage, CMV-specific clones were enriched in GZMK⁺ CD8⁺ T cells and CD8⁺ TEMRA cells, whereas in the CD4⁺ lineage, Th1 cells showed clonal expansion alongside CD4⁺ TEMRA cells.</p> Conclusions <p>This multi-cohort integrative study defines the cellular and clonal signatures of latent CMV in humans and identifies GZMK⁺ CD8⁺ T cells and Th1 cells as previously underappreciated components of the CMV response.</p>

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CMV-specific clonal expansion in human Th1 and GZMK⁺ CD8⁺ T cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Titas Grabauskas,
  • Luke Trinity,
  • Chris P. Verschoor,
  • Djamel Nehar-Belaid,
  • Radu Marches,
  • Giray Eryilmaz,
  • Avinash S. Mahajan,
  • Sathyabaarathi Ravichandran,
  • Asa Thibodeau,
  • Emilie Picard,
  • Chia-Ling Kuo,
  • Kenneth E. Schmader,
  • Cathleen Colon-Emeric,
  • Heather E. Whitson,
  • Silke Paust,
  • Adolfo García-Sastre,
  • Gur Yaari,
  • Jacques Banchereau,
  • George A. Kuchel,
  • Duygu Ucar

摘要

Background

Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latency and becomes increasingly prevalent with age. To systematically delineate CMV-associated immune remodeling at single-cell resolution, we analysed six human cohorts (including two newly established cohorts) using single-cell RNA sequencing, T cell receptor (TCR) sequencing, and flow cytometry.

Results

We identified novel CMV-associated changes in cell frequencies, including increases in GZMK⁺ CD8⁺ T cells and atypical B cells, and a reduction in CD56dim NK cells, in addition to the canonical expansion of CD4⁺/CD8⁺ TEMRA and adaptive NK cells. Longitudinal profiling of an individual who seroconverted revealed rapid CMV-driven shifts in circulating immune cell frequencies. Leveraging a recently published CMV-specific TCRβ database, combined with predictive modeling (CMVerify), we identified novel CMV-specific clonal expansions that were reproduced across two independent cohorts. In the CD8⁺ lineage, CMV-specific clones were enriched in GZMK⁺ CD8⁺ T cells and CD8⁺ TEMRA cells, whereas in the CD4⁺ lineage, Th1 cells showed clonal expansion alongside CD4⁺ TEMRA cells.

Conclusions

This multi-cohort integrative study defines the cellular and clonal signatures of latent CMV in humans and identifies GZMK⁺ CD8⁺ T cells and Th1 cells as previously underappreciated components of the CMV response.