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The Journal of Immunology, 2005, 175: 4886-4896.
Copyright © 2005 by The American Association of Immunologists

Memory T Cells and Their Costimulators in Human Allograft Injury1

Stephen L. Shiao*, Jennifer M. McNiff{dagger},{ddagger} and Jordan S. Pober2,*,{dagger},{ddagger},§

* Section of Immunobiology, {dagger} Department of Dermatology, {ddagger} Department of Pathology, and § Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06520

Both CD4+ and CD8+ human memory but not naive T cells respond to allogeneic human dermal microvascular endothelial cells (HDMEC) in vitro by secreting cytokines and by proliferating. Several recently identified costimulators, namely, 4-1BB ligand, ICOS ligand, and OX40 ligand, are up-regulated on cultured HDMEC in response to TNF or coculture with allogeneic T cells. Blockade of these costimulators each partially reduces IFN-{gamma} and IL-2 secretion and proliferation of previously resting memory T cells. The effects of these costimulators are overlapping but not identical. Memory but not naive T cells are the principal effectors of microvascular injury in human skin allografts following adoptive transfer into immunodeficient mice. Furthermore, blocking 4-1BB ligand, ICOS ligand, or OX40 ligand in this model reduces human skin allograft injury and T cell effector molecule expression. These data demonstrate that human memory T cells respond to microvascular endothelial cells and can injure allografts in vivo without priming. Furthermore, several recently described costimulators contribute to these processes.




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