title: Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD.
abstract: The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;
authors.forename: Ana C
authors.initials: AC
authors.lastname: Alho
authors.affiliation: Department of Biostatistics and Computational Biology, and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA; and Harvard Chan School of Public Health, Boston, MA.
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Marie J
authors.initials: MJ
authors.lastname: Chammas
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Carol G
authors.initials: CG
authors.lastname: Reynolds
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Tiago R
authors.initials: TR
authors.lastname: Matos
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Edouard
authors.initials: E
authors.lastname: Forcade
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whangbo
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;
authors.forename: Joao F
authors.initials: JF
authors.lastname: Lacerda
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*; D014184:Transplantation, Homologous / Q000009:adverse effects; D055815:Young Adult