CD99 signals caspase-independent T cell death

Death signaling by Fas and TNF receptors plays a major role in the control of activated mature T cells. However, the nature of the death receptors, wh ich may be used by the immune system to control T cells that have not acqui red susceptibility to Fas ligand or TNF, is not established. In this study, we demonstrate that engagement of distinct epitopes on CD99 rapidly induce s T cell death by a novel caspase-independent pathway. A new mAb to these C D99 epitopes, Ad20, induces programmed cell death of transformed T cells as determined by morphological changes, phosphatidylserine exposure on the ce ll surface, and uptake of propidium iodide. In general, ligation of CD99 in duced kinetically faster and more profound death responses as compared with the impact of anti-Fas and TNF-related apoptosis-inducing ligand (TRAIL). Ad20-induced programmed cell death was observed with seven of eight T cell lines examined, and notably, only two of these were distinctly responsive t o anti-Fas and TRAIL. CD99-mediated death signaling proceeded independently of functional CD3, CD4, CD45, and p56(lck), revealed distinctions from CD4 7-mediated T cell death responses, and was not influenced by interference w ith CD47 signaling. In contrast to the effect on transformed T cell lines, Ad20-induced death responses were not observed with normal peripheral T cel ls. Thus, our data suggest that CD99 is linked to a novel death pathway tha t may have biologic relevance in control of early T cells.