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CD99 signals caspase-independent T cell death
R D Pettersen1, G Bernard, M K Olafsen
1Department of Pediatric Research and Pediatrics, National Hospital, Oslo, Norway. rolf.pettersen@klinmed.uio.no
Abstract:
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, which may be used by the immune system to control T cells that have not acquired susceptibility to Fas ligand or TNF, is not established. In this study, we demonstrate that engagement of distinct epitopes on CD99 rapidly induces T cell death by a novel caspase-independent pathway. A new mAb to these CD99 epitopes, Ad20, induces programmed cell death of transformed T cells as determined by morphological changes, phosphatidylserine exposure on the cell surface, and uptake of propidium iodide. In general, ligation of CD99 induced 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 to anti-Fas and TRAIL. CD99-mediated death signaling proceeded independently of functional CD3, CD4, CD45, and p56(lck), revealed distinctions from CD47-mediated T cell death responses, and was not influenced by interference with CD47 signaling. In contrast to the effect on transformed T cell lines, Ad20-induced death responses were not observed with normal peripheral T cells. Thus, our data suggest that CD99 is linked to a novel death pathway that may have biologic relevance in control of early T cells.
Insights
Researchers discovered that engaging specific CD99 epitopes rapidly triggers T cell death via a new caspase-independent pathway. This CD99-mediated T cell death is faster and more potent than Fas or TRAIL signaling, suggesting a novel mechanism for controlling early T cells.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Fas and TNF receptors are crucial for controlling mature T cells.
- The mechanisms for immune system control of T cells lacking Fas/TNF susceptibility are unknown.
Purpose of the Study:
- To investigate novel death receptors for T cell control.
- To characterize the T cell death pathway induced by CD99.
Main Methods:
- Utilized a new monoclonal antibody (mAb), Ad20, targeting specific CD99 epitopes.
- Assessed T cell death using morphological changes, phosphatidylserine exposure, and propidium iodide uptake.
- Compared CD99-mediated death with Fas and TNF-related apoptosis-inducing ligand (TRAIL) signaling.
Main Results:
- Engagement of CD99 epitopes rapidly induced programmed T cell death in transformed T cell lines.
- CD99-mediated death was faster and more profound than anti-Fas and TRAIL.
- This pathway was independent of CD3, CD4, CD45, p56(lck), and CD47 signaling.
- Normal peripheral T cells did not exhibit Ad20-induced death.
Conclusions:
- CD99 ligation activates a novel, caspase-independent T cell death pathway.
- This pathway is distinct from Fas, TRAIL, and CD47-mediated death.
- CD99 may play a role in the immune control of early T cells.