Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation

Abstract

Key Points• T SCM lymphocytes are preferentially generated from naive precursors in vivo early after haploidentical HSCT.• T SCM represent relevant novel players in the diversification of immunological memory after haploidentical HSCT.Memory stem T cells (T SCM ) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked T SCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived T SCM are highly enriched early after HSCT. We showed at the antigenspecific and clonal level that T SCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of T SCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting T SCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT. (Blood. 2015;125(18):2865-2874

Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide

“…14,15 The patient was able to overcome CMV ( Figure 6A) reactivation. Based on his good clinical condition (no sign or symptoms of CMV disease), and because we observed a spike in the CMV-specific CD8 1 host T lymphocyte count, no further antiviral treatment was used.…”

“…14,15 Furthermore, our ability to avoid the use of immune-suppressive drugs after Cy administration might help control relapse through the activity of the host and donor T cells, as well as the substantial level of NK cells. Clearly, while no statement regarding relapse can be made based on our limited data, if these patients or future patients treated by this protocol do relapse, they would remain eligible for further treatment with immune cells from the original donor, including chimeric antigen receptor T cells, NK cells, or simply donor lymphocyte infusion.…”

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

“…Simultaneously, T memory stem cells can give rise to more differentiated central memory T cells (T CM cells), effector memory T cells (T EM cells), and terminally differentiated effector memory T cells (T TDEM cells) through transitional proliferation and effectively reconstitute cellular immunity in immunocompromised hosts during serial transplantation experiments in animal models (23). A recent study also showed that T SCM cells are able to persist and to preserve their precursor potential for up to 12 years after lymphocyte infusion in immunodeficient patients (24) and play important roles for regenerating the memory T cell pool after hematopoietic stem cell transplantation (25,26). So far, T memory stem cells recognizing influenza virus (Flu), cytomegalovirus (CMV), and tumor antigens have been identified (20), but it is likely that T memory stem cells contribute to cellular immune responses against virtually any type of antigen.…”

Halfway there: the past, present and future of haploidentical transplantation

“…Several important studies have examined the effects of PTCy and the regeneration of T-cell subset following transplant. 24,85,86 Work is ongoing on other cellular subsets, including natural killer cells. 87 Relapse after transplant continues to be a challenge.…”