Role of naïve-derived T memory stem cells in T cell reconstitution following allogeneic transplantation

Early T cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Post-transplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T cell population in the early days following haploidentical transplantation combined with pt-Cy, and precede the expansion of effector cells. Transferred naïve, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that post-transplant TSCM cells originate from naïve precursors. Moreover, donor naïve T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generated detectable recall responses but only in the presence of the cognate antigen. We thus define the cellular basis of T cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naïve-derived TSCM cells in the clinical setting to overcome immunodeficiency.