Role of naive-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. Posttransplant 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 naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive 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 generate 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 naive-derived TSCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580.
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy;
Alessandra
http://orcid.org/0000-0001-6615-0026
A
Roberto
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Luca
L
Castagna
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy;
Veronica
V
Zanon
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Stefania
S
Bramanti
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Roberto
R
Crocchiolo
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;
James E
JE
McLaren
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Sara
S
Gandolfi
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy;
Paolo
P
Tentorio
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Barbara
B
Sarina
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Inna
I
Timofeeva
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy;
Armando
A
Santoro
Hematology and Bone Marrow Transplant Unit, Humanitas Cancer Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy;
Carmelo
C
Carlo-Stella
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy;
Benedetto
B
Bruno
Department of Haematology and Pediatric Onco-Haematology, Istituto Nazionale Tumori, Milan, Italy; and.
Cristiana
C
Carniti
Department of Haematology and Pediatric Onco-Haematology, Istituto Nazionale Tumori, Milan, Italy; and.
Paolo
P
Corradini
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;
Emma
E
Gostick
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;
Kristin
K
Ladell
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom;
David A
DA
Price
ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Mario
M
Roederer
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy;
Domenico
http://orcid.org/0000-0001-6147-0952
D
Mavilio
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy;
Enrico
http://orcid.org/0000-0002-1964-7678
E
Lugli
D000328:Adult; D001782:Blood Donors; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D018655:Lymphocyte Count; D038041:Lymphopoiesis; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D014181:Transplantation Immunology / Q000276:immunology; D014184:Transplantation, Homologous