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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-06-1904.
Submitted June 27, 2002
Accepted January 8, 2003
Responding naive T cells differ in their sensitivity to Fas-engagement: early death of many T cells is compensated by costimulation of surviving T cells
Mikael Maksimow, Minna Santanen, Sirpa Jalkanen, and Arno Hanninen*
MediCity Research Laboratory, University of Turku, Turku, Finland
Department in Turku, National Public Health Institute, Turku, Finland
* Corresponding author; email: arhanni{at}utu.fi.
Engagement of Fas (CD95) induces death of activated T cells but can also potentiate T-cell response to CD3-ligation. Yet, the effects of Fas-mediated signals on activation of naive T cells have remained controversial. We followed naive T cells responding under Fas-ligation. Ligation of Fas simultaneously with activation by antigen-bearing dendritic cells promoted early death in half of the responding naive murine CD4 T cells. Surprisingly, it simultaneously accelerated cell-division and IFN- production among surviving T cells. These cells developed quickly an activation-associated phenotype (CD44hi, CD62Llo), responded vigorously to antigen-rechallenge, were partially resistant to subsequent induction of cell-death via Fas, and were long-lived in vivo. Compared to the cells becoming apoptotic, the surviving cells expressed lower levels of Fas and higher levels of TCR, CD4 and IL2R. Their survival was associated with expression of antiapoptotic c-FLIP, Bcl-xL and Bcl-2. Thus, at the time of T-cell activation there is a subtle balance in the effects of Fas-ligation that differs on a cell-to-cell basis. Factors that predict cell-survival include expression levels of Fas, TCR, CD4 and IL2R. Early death of some cells and a pronounced response of the surviving cells suggest that Fas-ligation can both up- and downregulate a primary T-cell response.
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