Activation-induced apoptosis of mature T cells is dependent upon the level of surface TCR but not on the presence of the CD3 zeta ITAM.
Activation-induced cell death (AICD) occurs primarily in recently activated T cells after a second TCR triggering. Since a threshold in the activation status may be critical for AICD, it is likely that the CD3 ITAM, docking sites for tyrosine kinases, regulate AICD. A 'threshold model' for AICD was tested by using two targeted mutant mouse strains lacking either the zeta chain (CD3zeta-/-) or the ITAM of the zeta chain (CD3zeta-/-:Tgzetadelta67-150). Although the T cells from the CD3zeta-/- mice express extremely low levels of surface TCR, a subpopulation (approximately 18%) of activated T cells could be induced to express TCR/FcepsilonRI gamma by using a powerful polyclonal activation protocol. These activated TCR/FcRI gamma T cells were capable of undergoing AICD, but its induction required 10 times as much anti-CD3epsilon mAb as that required for AICD of wild-type T cells. Thus, the intensity of AICD correlated with the level of CD3 expression and was less efficient with activated, CD3zeta(-/-)-derived T cells. By contrast, AICD of T cells from the CD3zeta-/-:Tgzetadelta67-150 mice could be induced with low doses of anti-CD3epsilon mAb and the extent of AICD was comparable to T cells from wild-type mice. The AICD induced in T cells from CD3-/-, CD3zeta-/-:Tgzetadelta67-150 and normal controls was specifically inhibited by Fas-Ig fusion proteins. Our data support the 'threshold model' of AICD by demonstrating that AICD is controlled by the strength of T cell activation.
She
J
J
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Matsui
K
K
Terhorst
C
C
Ju
S T
ST
D000818:Animals; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism
D017252:CD3 Complex; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine