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*
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455;
Department of Opthalmology, Louisiana State University Medical Center, New Orleans, LA 70112;
Immunomodulation Research Center, University of Ulsan, Ulsan, Korea; and
Immunex, Seattle, WA 98101
4-1BB is expressed on activated CD4+ and
CD8+ T cells; its ligand, 4-1BB ligand is expressed on
APCs. Despite expression on both T cell subpopulations, 4-1BB has been
reported to predominantly affect CD8+ T cell responses. By
quantifying graft-vs-host disease alloresponses in vivo, we demonstrate
that both CD4+ and CD8+ T cell-mediated
alloresponses are regulated by 4-1BB/4-1BB ligand interactions to
approximately the same extent. 4-1BB receptor-facilitated
CD4+ T cell-mediated alloresponses were partly CD28
independent. In two distinct marrow graft rejection systems, host
CD8+ and CD4+ T cells each separately
contributed to host anti-donor T cell-mediated allograft rejection.
4-1BB mAb increased the graft-vs-leukemia effect of a suboptimal
number of donor splenocytes given later post bone marrow
transplantation by bolstering allogeneic responses resulting in
leukemia elimination. In summary, 4-1BB ligation is a potent regulator
of CD4+ and CD8+ T cell-mediated allogeneic
responses in vivo. Modifying the ligation of 4-1BB represents a new
approach to altering the graft-vs-host disease and graft-vs-leukemia
effects of allogeneic T cells post bone marrow
transplantation.
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