title: Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation.
abstract: Delayed T-cell recovery is an important complication of allogeneic bone marrow transplantation (BMT). We demonstrate in murine models that donor BM-derived T cells display increased apoptosis in recipients of allogeneic BMT with or without GVHD. Although this apoptosis was associated with a loss of Bcl-2 and Bcl-X(L) expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- or Bax-, or BM-overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor-derived T cells. CD44 expression was associated with an increased percentage of BM-derived apoptotic CD4(+) and CD8(+) T cells. Transplantation of RAG-2-eGFP-transgenic BM revealed that proliferating eGFP(lo)CD44(hi) donor BM-derived mature T cells were more likely to undergo to apoptosis than nondivided eGFP(hi)CD44(lo) recent thymic emigrants in the periphery. Finally, experiments using carboxyfluorescein succinimidyl ester-labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44(hi) phenotype was associated with increased apoptosis in T cells. We conclude that apoptosis of newly generated donor-derived peripheral T cells after an allogeneic BMT contributes to delayed T-cell reconstitution and is associated with CD44 expression and rapid spontaneous proliferation by donor BM-derived T cells.
authors.affiliation: Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: S Onder
authors.initials: SO
authors.lastname: Alpdogan
authors.forename: Sydney X
authors.initials: SX
authors.lastname: Lu
authors.forename: Neel
authors.initials: N
authors.lastname: Patel
authors.forename: Suzanne
authors.initials: S
authors.lastname: McGoldrick
authors.forename: David
authors.initials: D
authors.lastname: Suh
authors.forename: Tulin
authors.initials: T
authors.lastname: Budak-Alpdogan
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: Jeremy
authors.initials: J
authors.lastname: Grubin
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.forename: Gabrielle L
authors.initials: GL
authors.lastname: Goldberg
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hubbard
authors.forename: Adam A
authors.initials: AA
authors.lastname: Kochman
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000534:rehabilitation; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D014184:Transplantation, Homologous; D051028:bcl-2-Associated X Protein / Q000235:genetics; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
chemical_list: D018960:Hyaluronan Receptors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D051028:bcl-2-Associated X Protein; D019014:fas Receptor