Infusion of select leukemia-reactive TCR Vbeta+ T cells provides graft-versus-leukemia responses with minimization of graft-versus-host disease following murine hematopoietic stem cell transplantation

Abstract

T-cell receptor (TCR) Vbeta-expression analysis by complementarity-determining region 3 (CDR3)-size spectratyping can identify the reactive populations in an immunologic response. This analysis was used in this study to characterize the Vbeta responses of C57BL/6 (B6) CD4+ and CD8+ T cells directed to either alloantigen (against [B6xDBA/2]F1; anti-H2d) or the syngeneic myeloid leukemia MMB3.19. Vbeta families exhibiting reactivity to the leukemia cells were then enriched for and administered in both syngeneic and allogeneic hematopoietic stem cell transplantation (HSCT) models to assess in vivo graft-versus-leukemia (GVL) potential. In syngeneic transplants, enrichment for pools of selected Vbeta families (Vbeta7, -11, and -13) of T cells or for a single Vbeta family (Vbeta7) of CD4+ T cells conveyed a beneficial GVL response to the recipients. Furthermore, in the haploidentical allogeneic model, both Vbeta6,7-enriched donor B6 T cells and Vbeta7-enriched CD4+ T cells exhibited significant GVL responses with concomitant minimization of graft-versus-host disease (GVHD) development compared with equal numbers of unfractionated T cells. These results suggest that CDR3-size spectratype analysis of and subsequent selection from donor T-cell repertoires can be an effective approach to separate GVL and GVHD potential following allogeneic HSCT.