Healthy-like CD4+ Regulatory and CD4+ Conventional T-Cell Receptor Repertoires Predict Protection from GVHD Following Donor Lymphocyte Infusion

Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes in the clonal T-cell receptor (TCR) repertoire. To investigate this, we analyzed T cells in a cohort of 21 patients receiving DLI after alloHSCT. We performed deep T-cell receptor beta (TRB) sequencing of sorted CD4(+)CD25(+)CD127(low) regulatory T cells (T-reg cells) and CD4(+) conventional T cells (T-con cells) in order to track longitudinal changes in the TCR repertoire. GVHD following DLI was associated with less diverse but clonally expanded CD4(+)CD25(+)CD127(low) T-reg and CD4(+) T-con TCR repertoires, while patients without GVHD exhibited healthy-like repertoire properties. Moreover, the diversification of the repertoires upon GVHD treatment was linked to steroid-sensitive GVHD, whereas decreased diversity was observed in steroid-refractory GVHD. Finally, the unbiased sample analysis revealed that the healthy-like attributes of the CD4(+)CD25(+)CD127(low) T-reg TCR repertoire were associated with reduced GVHD incidence. In conclusion, CD4(+)CD25(+)CD127(low) T-reg and CD4(+) T-con TRB repertoire dynamics may provide a helpful real-time tool to improve the diagnosis and monitoring of treatment in GVHD following DLI.

Automated summary

Donor lymphocyte infusion (DLI) can induce durable remission in relapsing patients after alloHSCT, but it carries the risk of graft-versus-host disease (GVHD). This study analyzed T cells in patients receiving DLI after alloHSCT and found that GVHD was associated with changes in the T-cell receptor (TCR) repertoire. The dynamics of CD4(+)CD25(+)CD127(low) regulatory T cells (T-reg cells) and CD4(+) conventional T cells (T-con cells) TCR repertoire could be helpful in diagnosing and monitoring GVHD following DLI.