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 β (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.