# γδ T cell characterisation in the long term after haematopoietic stem cell transplantation and its impact on CMV control and cGVHD severity

## TL;DR

This study shows that γδ T cells recover long-term after stem cell transplants, help control CMV, and may contribute to chronic GVHD severity.

## Contribution

The study reveals long-term γδ T cell reconstitution and its role in CMV control and cGVHD severity after stem cell transplantation.

## Key findings

- γδ T cells reconstitute with a normalised repertoire and sustained CMV control ability.
- Overrepresented donor-derived clonotypes and elevated HLA-DR+Vδ1+ T cells are linked to severe chronic GVHD.
- The TCR γ-chain composition in long-term survivors is largely restored with no significant diversity differences.

## Abstract

The clinical outcome after allogeneic haematopoietic stem cell transplantation (aHCT) relies greatly on the efficient recovery of T cells. Several studies have investigated the short‐term γδ T cell reconstitution and their role in clinical outcomes following haematopoietic stem cell transplantation. Nevertheless, their long‐term characteristics and impact have remained largely unknown.

We analysed γδ T cells from 20 recipient/donor pairs at phenotypic, clonotypic and functional levels to assess their reconstitution ≥ 8 years (median 18 years) post‐transplantation using high‐parameter flow cytometry and next‐generation sequencing of the TCR γ‐chain.

γδ T cells displayed comparable phenotypic characteristics between recipients and matching donors. The Vδ2+ subset showed a more activated phenotype and cytokine production, while the Vδ1+ and non‐Vδ2 T cells maintained long‐term CMV control. TCR γ‐chain composition in long‐term survivors was largely restored, with no significant differences in gene segment usage or diversity. A small cohort of recipients with severe chronic graft‐versus‐host disease (GVHD) showed overrepresented donor‐derived private clonotypes. Furthermore, we also found elevated HLA‐DR+Vδ1+ T cells in recipients with severe chronic GVHD.

Overall, γδ T cells reconstitute with a normalised repertoire, high functional capacity and sustained CMV control ability. An increased proportion of activated Vδ1+ T cells correlates with chronic GVHD severity, indicating a potential therapeutic target.

In this study, we found that long‐term γδ T cell reconstitution post allogeneic haematopoietic stem transplantation (aHCT) reached a homeostatic state with a normalised TRG CDR3 repertoire. Importantly, γδ T cells remained functional and provided a long‐term control on cytomegalovirus (CMV) after aHCT. Additionally, some recipients exhibited overrepresented clonotypes and increased HLA‐DR expression on Vδ1 T cells, which are associated with severe chronic graft‐versus‐host disease (cGVHD).