title: Invariant NKT cell reconstitution in pediatric leukemia patients given HLA-haploidentical stem cell transplantation defines distinct CD4+ and CD4- subset dynamics and correlates with remission state.
abstract: Immune reconstitution plays a crucial role on the outcome of patients given T cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) for hematological malignancies. CD1d-restricted invariant NKT (iNKT) cells are innate-like, lipid-reactive T lymphocytes controlling infections, cancer, and autoimmunity. Adult mature iNKT cells are divided in two functionally distinct CD4(+) and CD4(-) subsets that express the NK receptor CD161 and derive from thymic CD4(+)CD161(-) precursors. We investigated iNKT cell reconstitution dynamics in 33 pediatric patients given hHSCT for hematological malignancies, with a follow-up reaching 6 y posttransplantation, and correlated their emergence with disease relapse. iNKT cells fully reconstitute and rapidly convert into IFN-γ-expressing effectors in the 25 patients maintaining remission. CD4(+) cells emerge earlier than the CD4(-) ones, both displaying CD161(-) immature phenotypes. CD4(-) cells expand more slowly than CD4(+) cells, though they mature with significantly faster kinetics, reaching full maturation by 18 mo post-hHSCT. Between 4 and 6 y post-hHSCT, mature CD4(-) iNKT cells undergo a substantial expansion burst, resulting in a CD4(+)<CD4(-) NKT cell ratio similar to that found in healthy adults. In contrast with patients maintaining remission, iNKT cells failed to reconstitute in all eight patients experiencing disease relapse. These findings define the peripheral dynamics of human iNKT cells and suggest a contribution of these cells to maintain remission, possibly via early IFN-γ provision. Adoptive transfer of donor-derived iNKT cells into HLA-haploidentical patients failing to reconstitute these cells might represent a novel therapeutic option to prevent leukemia recurrence.
authors.affiliation: Experimental Immunology Unit, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: de Lalla
authors.forename: Anna
authors.initials: A
authors.lastname: Rinaldi
authors.forename: Daniela
authors.initials: D
authors.lastname: Montagna
authors.forename: Laura
authors.initials: L
authors.lastname: Azzimonti
authors.forename: Maria Ester
authors.initials: ME
authors.lastname: Bernardo
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sangalli
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Paganoni
authors.forename: Rita
authors.initials: R
authors.lastname: Maccario
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Cesare-Merlone
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Dellabona
authors.forename: Giulia
authors.initials: G
authors.lastname: Casorati
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D006680:HLA Antigens / Q000008:administration & dosage / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D012074:Remission Induction; D055815:Young Adult
chemical_list: D006680:HLA Antigens