ANALYSIS OF EXPRESSION AND FUNCTION OF THE COSTIMULATORY MOLECULE 4–1BB IN ALLOIMMUNE RESPONSES1


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Abstract

Background.4–1BB (CD137) is a T cell costimulatory molecule that promotes T cell activation. In this study, we investigated the role of 4–1BB costimulation in allogeneic T cell responses.Methods.Vascularized heart transplantation, allogeneic mixed leukocyte reaction (MLR), and graft versus host disease models were used to examine 4–1BB and 4–1BBL expression. In addition, agonistic anti-4–1BB antibodies were used in MLR to functionally analyze T cell responses.Results.Using a heart transplant model, we found that 4–1BB and 4–1BBL transcripts were both expressed in rejecting cardiac grafts. In the allogeneic MLR, 4–1BB was expressed on both activated CD4 and CD8 T cells and 4–1BB was expressed on T cells after multiple cell divisions in vivo. Functionally, 4–1BB was a potent stimulator of proliferation, cytokine secretion, and CD25 expression by CD8 T cells, but 4–1BB signals had a weak effect on the proliferation of CD4 T cells. Because 4–1BB promoted the secretion of IL-2 and the expression of CD25 on CD8 T cells, we investigated whether IL-2 was the only factor whereby 4–1BB signals induced CD8 T cell proliferation. Although IL-2 was required for optimal CD8 T cell proliferation, 4–1BB also costimulated CD8 T cell proliferation independently of IL-2.Conclusions.This study demonstrates that 4–1BB is expressed on activated, maximally divided T cells and shows that 4–1BB promotes CD8 T cell proliferation by enhancing signals through the IL-2 receptor and by other mechanisms independent of the IL-2 pathway.

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