Assistant Professor of Medical Sciences (in Medicine), Principal Investigator Columbia University New York, New York, United States
Abstract Text: The role of γδ T cells in intestinal transplantation (ITx) is unclear. We performed phenotypic and clonal tracking of recipient-derived γδ T cells after human ITx in blood and intestinal grafts by integrating flow cytometry and sequencing platforms. We previously demonstrated that donor T-cell blood macrochimerism (peak level ≥4%) is associated with less rejection and slower replacement of donor T-cells in the intestinal graft by the recipient. With γδ T cells, we found that, regardless of macrochimerism status, turnover dynamics were more rapid in patients with younger donors. Graft-repopulating recipient γδ T cells showed effector (Teff) phenotypes early post-Tx and gradually acquired resident-memory (TRM) phenotypes with “private” non-Vγ9δ2 clonotypes. Single-cell profiling of recipient γδ T cells from 2 quiescent and 4 rejecting intestinal mucosal specimens late post-Tx were enriched for interchangeable Teff/TRM clusters, with higher cytotoxic Teff gene expression during rejection. In one patient, the top-dominant Vδ2 sequence (mainly Vγ5δ2) in the blood during quiescence was found at low frequencies in early quiescent graft samples but as the top-dominant sequence in later rejecting samples, suggesting active exchange of γδ T cells between the blood and graft during rejection. TCR distance analysis using the tcrdist3 algorithm suggested that this top-dominant sequence unlikely recognizes MICA or CD1d, given high distance scores (>150) from MICA- or CD1d-specific TCRδs, but has structural similarity with some TCRδs apparently stimulated by cytokines produced by autologous αβ T cells, with distance scores as low as 48. Taken together, recipient γδ T cells may affect ITx outcomes.
