Oehme, Ina;
Neumann, Frank;
Bösser, Susanne;
Zörnig, Martin
Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection
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Medientyp:
E-Artikel
Titel:
Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection
Beteiligte:
Oehme, Ina;
Neumann, Frank;
Bösser, Susanne;
Zörnig, Martin
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>The cellular homologues of the viral anti‐apoptotic v‐FLIP proteins exist as a long (c‐FLIP<jats:sub>L</jats:sub>) and a short (c‐FLIP<jats:sub>S</jats:sub>) splice variant. While c‐FLIP<jats:sub>S</jats:sub> and v‐FLIP are composed solely of two death effector domains, c‐FLIP<jats:sub>L</jats:sub> contains an (inactive) caspase‐like domain in addition to these two death effector domains, thereby structurally resembling pro‐Caspase‐8. Both c‐FLIP<jats:sub>L</jats:sub> and c‐FLIP<jats:sub>S</jats:sub> suppress apoptosis by inhibiting Caspase‐8 activation, although at different levels of pro‐Caspase‐8 processing. To analyze the consequences of deregulated c‐FLIP<jats:sub>S</jats:sub> expression <jats:italic>in vivo</jats:italic>, we established <jats:italic>lck</jats:italic> FLIP<jats:sub>S</jats:sub>‐transgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L‐induced apoptosis was impaired in <jats:italic>lck</jats:italic> FLIP<jats:sub>S</jats:sub>‐transgenic T cells, indicating the functionality of the FLIP<jats:sub>S</jats:sub> transgene. Remarkably, activation‐induced cell death of transgenic T cells was unaffected, despite the observed inhibition of CD95‐induced T cell death. Thymic and splenic cell numbers as well as CD4/CD8 cellularity were normal in <jats:italic>lck</jats:italic> FLIP<jats:sub>S</jats:sub>‐transgenic animals, which in contrast to CD95‐deficient mice do not accumulate Thy1<jats:sup>+</jats:sup> B220<jats:sup>+</jats:sup> CD4<jats:sup>–</jats:sup> CD8<jats:sup>–</jats:sup> peripheral T cells. c‐FLIP<jats:sub>S</jats:sub> overexpression leads to a significant decrease in activation‐induced T cell proliferation <jats:italic>in vitro</jats:italic>. Despite the capacity of FLIP<jats:sub>S</jats:sub> to inhibit CD95‐induced apoptosis, T cell lymphomagenesis is not observed in <jats:italic>lck</jats:italic> FLIP<jats:sub>S</jats:sub>‐transgenic mice. Interestingly, the Vβ8<jats:sup>+</jats:sup> memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific <jats:italic>in vivo</jats:italic> function for FLIP<jats:sub>S</jats:sub> in the maintenance of restimulated T cells.</jats:p>