CD47 signals T cell death

Activation-induced death of T cells regulates immune responses and is consi dered to involve apoptosis induced by ligation of Fas and TNF receptors, Th e role of other receptors in signaling T cell death is less clear. In this study we demonstrate that activation of specific epitopes on the Ig variabl e domain of CD47 rapidly induces apoptosis of T cells, A new mAb, Ad22, to this site induces apoptosis of Jurkat cells and CD3 epsilon-stimulated PBMC , as determined by morphological changes, phosphatidylserine exposure on th e cell surface, uptake of propidium iodide, and true counts by flow cytomet ry, In contrast, apoptosis was not observed following culture with anti-CD4 7 mAbs 2D3 or B6H12 directed to a distant or closely adjacent region, respe ctively. CD47-mediated cell death was independent of CD3, CD4, CD45, or p56 (lck) involvement as demonstrated by studies with variant Jurkat cell lines deficient in these signaling pathways, However, coligation of CD3 epsilon and CD47 enhanced phosphatidylserine externalization on Jurkat cells with f unctional CD3, Furthermore, normal T cells required preactivation to respon d with CD47-induced apoptosis, CD47-mediated cell death appeared to proceed independent of Fas or TNF receptor signaling and did not involve character istic DNA fragmentation or requirement for IL-1 beta-converting enzyme-like proteases or CPP32, Taken together, our data demonstrate that under approp riate conditions, CD47 activation results in very rapid T cell death, appar ently,mediated by a novel apoptotic pathway. Thus, CD47 may be critically i nvolved in controlling the fate of activated T cells.