Human effector memory CD4+ T cells directly recognize allogeneic endothelial cells in vitro and in vivo

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-gamma within 48 It in response to allogeneic ECs than do T-CM. In contrast, T-EM and T-CM secrete comparable amounts of IFN-gamma 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-gamma-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-gamma 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-gamma 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-gamma. We conclude that human CD4(+) T-EM directly recognize and respond to allogeneic EC in vitro by secreting IFN-gamma 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.