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,
* Department of Immunobiology,
Department of Dermatology, and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520; and
Cambridge University, Cambridge, United Kingdom
The frequency of circulating alloreactive human memory T cells correlates with allograft rejection. Memory T cells may be divided into effector memory (TEM) and central memory (TCM) cell subsets, but their specific roles in allograft rejection are unknown. We report that CD4+ TEM (CD45RO+CCR7–CD62L–) can be adoptively transferred readily into C.B-17 SCID/bg mice and mediate the destruction of human endothelial cells (EC) in vascularized human skin grafts allogeneic to the T cell donor. In contrast, CD4+ TCM (CD45RO+CCR7+CD62L+) are inefficiently transferred and do not mediate EC injury. In vitro, CD4+ TEM secrete more IFN-
within 48 h in response to allogeneic ECs than do TCM. In contrast, TEM and TCM secrete comparable amounts of IFN- in response to allogeneic monocytes (Mo). In the same cultures, both TEM and TCM produce IL-2 and proliferate in response to IFN--treated allogeneic human EC or Mo, but TCM respond more vigorously in both assays. Blockade of LFA-3 strongly inhibits both IL-2 and IFN- secretion by CD4+ TEM cultured with allogeneic EC but only minimally inhibits responses to allogeneic Mo. Blockade of CD80 and CD86 strongly inhibits IL-2 but not IFN- production by in response to allogeneic EC or Mo. Transduction of EC to express B7-2 enhances allogeneic TEM production of IL-2 but not IFN-. We conclude that human CD4+ TEM directly recognize and respond to allogeneic EC in vitro by secreting IFN- and that this response depends on CD2 but not CD28. Consistent with EC activation of effector functions, human CD4+ TEM can mediate allogeneic EC injury in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Jordan S. Pober, 401D Amistad, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06509. E-mail address: jordan.pober{at}yale.edu
2 Abbreviations used in this paper: EC, endothelial cell; TCM, central memory T cell; TEM, effector memory T cell; Mo, monocyte.
This article has been cited by other articles:
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  J. D. Walker, C. L. Maier, and J. S. Pober Cytomegalovirus-Infected Human Endothelial Cells Can Stimulate Allogeneic CD4+ Memory T Cells by Releasing Antigenic Exosomes J. Immunol., February 1, 2009; 182(3): 1548 - 1559. [Abstract] [Full Text] [PDF]
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 D. A. Rao, R. E. Eid, L. Qin, T. Yi, N. C. Kirkiles-Smith, G. Tellides, and J. S. Pober Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection J. Exp. Med., December 22, 2008; 205(13): 3145 - 3158. [Abstract] [Full Text] [PDF]
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T. D. Manes and J. S. Pober Antigen Presentation by Human Microvascular Endothelial Cells Triggers ICAM-1-Dependent Transendothelial Protrusion by, and Fractalkine-Dependent Transendothelial Migration of, Effector Memory CD4+ T Cells J. Immunol., June 15, 2008; 180(12): 8386 - 8392. [Abstract] [Full Text] [PDF]
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