Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide

Abstract

Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (<i>n</i> = 74) and antigen receptor sequencing (<i>n</i> = 35) in recipients of myeloablative, HLA-matched allogeneic BM transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower T cell receptor β (<i>TRB</i>) repertoire diversity than input donor repertoires. Recovering B cells were predominantly naive with immunoglobulin heavy chain locus (<i>IGH</i>) repertoire diversity similar to donors. Numerical T cell reconstitution and <i>TRB</i> diversity were strongly associated with recipient cytomegalovirus seropositivity. Global similarity between input donor and recipient posttransplant repertoires was uniformly low at 1-2 months after transplant but increased over the balance of the first posttransplant year. Blood <i>TRB</i> repertoires at ≥3 months after transplant were often dominated by clones present in the donor blood/marrow memory CD8⁺ compartment. Limited overlap was observed between the <i>TRB</i> repertoires of T cells infiltrating the skin or gastrointestinal tract versus the blood. Although public <i>TRB</i> sequences associated with herpesvirus- or alloantigen-specific CD8⁺ T cells were detected in some patients, posttransplant <i>TRB</i> and <i>IGH</i> repertoires were unique to each individual. These data define the immune dynamics occurring after PTCy and establish a benchmark against which immune recovery after other transplantation approaches can be compared.