Paclitaxel inhibits killing by murine cytotoxic T lymphocytes in vivo but not in vitro.
To kill antigen-specific target cells (TCs), cytotoxic T lymphocytes (CTLs) reorganise their microtubule cytoskeleton to deliver lytic granules to the TCs. We used two drugs that stabilise microtubules, paclitaxel and peloruside, to determine how the stabilising microtubule network affects CTL function in vitro and in vivo. In vitro, neither paclitaxel nor peloruside inhibited antigen-specific killing, lytic granule delivery to the cell surface, nor interferon-gamma release by murine CTLs. In contrast, in an in vivo murine model of antigen-induced killing, a single dose of paclitaxel had a significant inhibitory effect on killing by CTLs. Furthermore, the inhibitory effect of paclitaxel was not caused by specific deletion of the effector CTL population in drug-treated mice. The findings reveal that microtubule-stabilising drug treatment can lead to immediate impairment of CTL function without affecting lytic granule release. The results also suggest that patients undergoing taxane anti-cancer therapy may be impaired in their ability to fight infection before the anti-mitotic effects of paclitaxel are apparent.
Robinson
Marcus James
MJ
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Ronchese
Franca
F
Miller
John H
JH
La Flamme
Anne Camille
AC
D000818:Animals; D000941:Antigens / Q000276:immunology; D017637:Clonal Deletion / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000276:immunology; D008938:Mitosis / Q000187:drug effects* / Q000276:immunology; D018448:Models, Immunological; D017239:Paclitaxel / Q000494:pharmacology*; D022142:Secretory Vesicles / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050257:Tubulin Modulators / Q000494:pharmacology*
D000941:Antigens; D050257:Tubulin Modulators; D007371:Interferon-gamma; D017239:Paclitaxel