Blazar B R, Kwon B S, Panoskaltsis-Mortari A, Kwak K B, Peschon J J, Taylor P A
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455, USA.
J Immunol. 2001 Mar 1;166(5):3174-83. doi: 10.4049/jimmunol.166.5.3174.
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. alpha 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.
4-1BB在活化的CD4(+)和CD8(+) T细胞上表达；其配体4-1BB配体在抗原呈递细胞上表达。尽管在两个T细胞亚群上均有表达，但据报道4-1BB主要影响CD8(+) T细胞应答。通过在体内定量移植物抗宿主病同种异体反应，我们证明CD4(+)和CD8(+) T细胞介导的同种异体反应均受4-1BB/4-1BB配体相互作用的调节，程度大致相同。4-1BB受体促进的CD4(+) T细胞介导的同种异体反应部分不依赖于CD28。在两个不同的骨髓移植排斥系统中，宿主CD8(+)和CD4(+) T细胞各自分别促成宿主抗供体T细胞介导的同种异体移植排斥。α4-1BB单克隆抗体通过增强同种异体反应导致白血病消除，增强了骨髓移植后晚期给予的次优数量供体脾细胞的移植物抗白血病效应。总之，4-1BB连接是体内CD4(+)和CD8(+) T细胞介导的同种异体反应的有效调节剂。改变4-1BB的连接代表了一种改变骨髓移植后同种异体T细胞的移植物抗宿主病和移植物抗白血病效应的新方法。
