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.
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-gamma (IFN-gamma) production among surviving T cells. These cells developed quickly an activation-associated phenotype (CD44(hi), CD62L(lo)), 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-X(L), 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.
Maksimow
Mikael
M
MediCity Research Laboratory, Turku University, Finland.
Santanen
Minna
M
Jalkanen
Sirpa
S
Hänninen
Arno
A
D019264:Adoptive Transfer; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death; D002470:Cell Survival; D005786:Gene Expression Regulation / Q000276:immunology; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor