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 h 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.
Shiao
Stephen L
SL
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Kirkiles-Smith
Nancy C
NC
Shepherd
Benjamin R
BR
McNiff
Jennifer M
JM
Carr
Edward J
EJ
Pober
Jordan S
JS
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018968:CD58 Antigens / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID
D018122:B7-1 Antigen; D018968:CD58 Antigens; D007376:Interleukin-2; D007371:Interferon-gamma