Listeria monocytogenes induces T cell receptor unresponsiveness via its pore-forming toxin listeriolysin O. Mus musculus

The success of many pathogens relies on their ability to circumvent the innate and adaptive immune defenses. How bacterial pathogens subvert host responses is not clear. Cholesterol-dependent cytolysins (CDCs) represent an expansive family of homologous pore-forming toxins produced by more than 20 Gram-positive bacterial species. Here we show that listeriolysin O (LLO), a prototype CDC produced by Listeria monocytogenes, inhibits antigen receptor-induced T cell proliferation. In vivo proliferation of OT II T cells was highly diminished in the presence of wild type but not the LLO-deficient bacteria. T cells pre-exposed to LLO ex vivo were also impaired in proliferation upon TCR activation in vivo and in vitro. Our results suggest that LLO-induced T cell unresponsiveness is due to the sub-threshold activation of T cells via the induction of a calcium-NFAT dependent transcriptional program that drives the expression of negative regulators of TCR signaling. Keywords: Listerilysin O, Ionomycin, 3 hours stimulation Overall design: Pooled primary CD4+ T cells isolated from spleen and mesenteric lymph nodes were incubated in either control (Ctrl) medium or medium containing 0.25 ug/ml listeriolysin O (LLO) or 1 uM Ionomycin (Iono) for 3 hours. Thereafter, cells were washed and RNA was prepared.