Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

Abstract

An effective T-cell receptor (TCR) repertoire diversification contributes to the success of hematopoietic cell transplantation (HCT). A full understanding of the patterns of T cell adaptive reconstitution may help in the discrimination of alloreactive responses. Herein, we prospectively studied the superstructure of TCR repertoire in 135 serial specimens from 35 patients receiving HCT for myeloid malignancies. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were the hallmarks of the T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3–based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post–allo-HCT phase, while autoreactive clones were more expanded in case of graft-versus-host disease occurrence. These findings shed light on post–allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.Keywords: TCR, adaptive immune competence, HCT, GVHD, clonal expansionKey points: • NGS deep TCR VβCDR3 sequencing allows for assessing clonal T-cell repertoire T-cell dynamics and tracing individual clonal specificities following hematopoietic stem cell transplantation.• After allogeneic hematopoietic cell transplantation, the restoration of TCR recognition spectrum is protracted and shaped by the post-transplant clinical course, diverging from the donor repertoire. • TCR VβCDR3 can serve as a quantifiable marker of specific immune responses defining a unique structure minimally overlapping with donor repertoire.