Differential regulation of activation-induced cell death in individual human T cell clones

Background: Restimulation of T lymphocytes via the TCR/CD3 complex can resu lt in CD95/CD95L-dependent activation-induced cell death (AICD). Although t he correlation of AICD sensitivity to the T helper 1 phenotype was confirme d in different studies, the underlying mechanism is still debated. Thus, it has been suggested that in Th2 cells, AICD resistance is controlled by a T CR-induced upregulation of the CD95-associated inhibitory phosphatase, FAP- 1. We and others demonstrated that AICD resistance is associated with a red uced surface expression of CD95L upon restimulation, Methods: Utilizing RT- PCR, Western blotting and flow cytometry, we analyzed time-dependent change s in levels of CD95L mRNA, cytosolic protein and surface expression in five long-term human T cell clones and polarized helper populations. Results: W e confirm that the inducible CD95L surface expression is lower or absent in all tested AICD-resistant clones as compared to sensitive cells. It is of interest that striking differences with respect to the activation-dependent inducibility of CD95L mRNA expression in individual resistant clones were observed. In addition, alterations in the expression of the inhibitory phos phatase FAP-1 or TCR-dependent changes in CD95 sensitivity in AlCD-resistan t clones could be ruled out as a mechanism for AICD resistance of human T c ell clones. Conclusions: (1) The data presented strongly support the previo us notion that AICD resistance of human T cell clones is mainly regulated b y a differential expression of CD95L. (2) Differential expression of CD95L on individual resistant clones results from a lack of mRNA induction in one set and from a markedly decreased surface expression of translated protein in another set of clones. (C) 2000 S. Karger AG, Basel.