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Abstract
Anti‐CD3ε monoclonal antibody induces programmed cell death of thymocytes and accelerates activation‐induced cell death (AICD) by apoptosis of matured or transformed T lymphocytes. However, the underlying molecular mechanism of this phenomenon is unclear. Therefore, we produced a chimera protein (termed CD8ε by fusing the extracellular and transmembrane domains of human CD8α to the intracellular domain of mouse CD3ε and expressed in CD8−Jurkat T cells. Stable cell lines of mutants expressing the motifs of Y170F, Y181F, and Y170F/Y181F in the CD3ε − ITAM were established. Experiments showed that apoptosis could be induced only in the T Jurkat cells with intact CD3ε intracellular domain, but not in the cells with the mutant CD8ε when stimulated with anti‐CD8α monoclonal antibody. This finding indicated that a single tyrosine mutation in CD3ε − ITAM blocked the signal transduction, causing the cell death by apoptosis when stimulated by CD8ε molecule. During the apoptotic process, we showed that expressions of CD95, CD95L and Nur77 were enhanced in stimulated TJK cells but not in control cells. In addition, the high expression of Nur77 kept pace with the onset of apoptosis of T‐cells mediated by CD8ε. We further showed that 3′‐phosphatidylinositol kinase (PI3K) were not only enhanced during T cell activation, but also in the AICD process. The results suggest that PI3K/Akt is not only a cell proliferation signal, but also a potential apoptosis regulator in T lymphocytes.
Nomenclature
| TCR: | = | T cell antigen receptor |
| ITAM: | = | immunoreceptor tyrosine‐based activation motif |
| AICD: | = | activation‐induced cell death |
| Y: | = | tyrosine |
| F: | = | phenylalanine |
| TJK: | = | Jurkat T cells with CD8ε chimera molecule expression |
| T1JK: | = | Jurkat T cells with the CD8ε mutation of Y170F |
| T2JK: | = | Jurkat T cells with the CD8ε mutation of Y181F |
| T3JK: | = | Jurkat T cells with the CD8ε mutation of Y170F/Y181F |
| Nur77: | = | steroid hormone receptor |
| PI3K: | = | phosphatidylinositol 3‐kinase |
| Akt: | = | protein kinase B |
| GSK‐3: | = | glycogen synthase kinase‐3 |
| CD95: | = | cluster determinant 95, also named as Fas/Apo‐1 |
| CD95L: | = | CD95 ligand |
| TNFR1: | = | tumor necrosis factor receptor 1 |
| NGFR: | = | neural growth factor receptor |
| TRAIL: | = | tumor necrosis factor related apoptosis inducing ligand |