Submitted February 29, 2008
Accepted August 8, 2008
Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay post-transplant T cell reconstitution after allogeneic bone marrow transplantation
S. Onder Alpdogan, Sydney X Lu, Neel Patel, Suzanne McGoldrick, David Suh, Tulin Budak-Alpdogan, Odette M. Smith, Jeremy Grubin, Christopher King, Gabrielle L. Goldberg, Vanessa M Hubbard, Adam A Kochman, and Marcel R.M. van den Brink*
Department of Medicine, Yale University School of Medicine, New York, NY, United States
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Medicine, Cancer Institute of New Jersey, New Brunswick, NJ, United States
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States
* Corresponding author; email: vandenbm{at}mskcc.org.
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. Though this apoptosis was associated with a loss of Bcl-2 and Bcl-XL expression, allogeneic recipients of donor BM deficient in Fas, 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 eGFPloCD44hi donor BM-derived mature T cells were more likely to undergo to apoptosis than non-divided eGFPhiCD44lo recent thymic emigrants in the periphery.
Finally, experiments using CFSE-labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44hi 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.
