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Human Effector Memory CD4⁺ T Cells Directly Recognize Allogeneic Endothelial Cells In Vitro and In Vivo

Stephen L. Shiao^*, Nancy C. Kirkiles-Smith^*, Benjamin R. Shepherd^*, Jennifer M. McNiff, Edward J. Carr and Jordan S. Pober^1,*,,

^* 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 (T_EM) and central memory (T_CM) cell subsets, but their specific roles in allograft rejection are unknown. We report that CD4⁺ T_EM (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⁺ T_CM (CD45RO⁺CCR7⁺CD62L⁺) are inefficiently transferred and do not mediate EC injury. In vitro, CD4⁺ T_EM secrete more IFN- within 48 h in response to allogeneic ECs than do T_CM. In contrast, T_EM and T_CM secrete comparable amounts of IFN- in response to allogeneic monocytes (Mo). In the same cultures, both T_EM and T_CM produce IL-2 and proliferate in response to IFN--treated allogeneic human EC or Mo, but T_CM respond more vigorously in both assays. Blockade of LFA-3 strongly inhibits both IL-2 and IFN- secretion by CD4⁺ T_EM 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 T_EM production of IL-2 but not IFN-. We conclude that human CD4⁺ T_EM 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⁺ T_EM can mediate allogeneic EC injury in vivo.

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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; T_CM, central memory T cell; T_EM, effector memory T cell; Mo, monocyte.

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