During intrathymic negative selection by clonal deletion, crosslinking of the T cell receptor (TCR) induces cell death by delivering an apoptotic signal(s) to the nucleus along a calcium-dependent pathway. We investigated the reactivity of early precursor-containing thymocytes to Ca2+-induced signals, and discovered a breakpoint in their sensitivity to calcium-mediated cell death (CMCD). CD25+ CD8−4− TCK− (triple negative [TN]) thymocytes stimulated with a calcium ionophore maintain their viability and precursor activity. By contrast, their immediate progeny, CD25−CD8lo4loTCRαβlo (triple low [TL]) cells react to calcium elevation by abrogation of precursor activity and apoptotic cell death. This developmental difference is specific for CMCD, since both CD25+ TN and CD25-TL cells are susceptible to steroid-induced apoptosis. The presence of bcl-2 mRNA correlates directly to the resistance to CMCD- CD25+ TN cells express it and CD25-TL cells do not. These experiments show that thymocytes become sensitive to Ca 2+-induced apoptosis as soon as they begin to express molecules that mediate thymic sdection, and suggest that a concomitant downregulation of bcl-2 may mediate this phenomenon.
ASJC Scopus subject areas
- Immunology and Allergy