Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation.
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.
Alpdogan
S Onder
SO
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Lu
Sydney X
SX
Patel
Neel
N
McGoldrick
Suzanne
S
Suh
David
D
Budak-Alpdogan
Tulin
T
Smith
Odette M
OM
Grubin
Jeremy
J
King
Christopher
C
Goldberg
Gabrielle L
GL
Hubbard
Vanessa M
VM
Kochman
Adam A
AA
van den Brink
Marcel R M
MR
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
D018960:Hyaluronan Receptors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D051028:bcl-2-Associated X Protein; D019014:fas Receptor