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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-06-1904.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4022-4028
IMMUNOBIOLOGY
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 Hänninen
From the MediCity Research Laboratory, Turku
University, Finland; and National Public Health Institute, Department
in Turku, Finland.
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 interferon- (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 with cells
becoming apoptotic, the surviving cells expressed lower levels of Fas
and higher levels of T-cell receptor (TCR), CD4, and interleukin-2
receptor (IL-2R). Their survival was associated with expression of
antiapoptotic cellular FLICE-inhibitory protein (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 IL-2R. Early death of some
cells and a pronounced response of the surviving cells suggest that Fas
ligation can both up- and down-regulate a primary T-cell response.
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