Combined activation signalling breaks established CD8+ T cell tolerance and results in effector CTL generation

Abstract

In the liver, soluble and gut-derived antigens are efficiently taken up by the resident antigen presenting cells, the liver sinusoidal endothelial cells (LSEC). Importantly, LSEC are capable of cross-presenting these antigens on MHC class I molecules to naïve CD8+ T cells. This cross-presentation results in the induction of antigen-specific T cell tolerance and the generation of a unique, tolerant CD8+ T cell subset. LSEC-tolerised CD8+ T cells are incapable of cytotoxic activity or production of effector cytokines. As we investigated the fate of tolerant CD8+ T cells in vivo, we discovered that LSEC-mediated T cell tolerance is not deletional. Rather, tolerant CD8+ T cells survive long time in vivo and reside in secondary lymphoid organs after tolerance induction by LSEC. Therefore, we wondered whether the initially established tolerant phenotype of LSEC primed T cells can be overruled and reconverted into an effector T cell type, e.g. by matured professional APCs. In response to viral infection, tolerant T cells responded with rapid proliferation and expansion. In addition, formerly tolerant T cells regained the capacity to produce IFN-g upon restimulation and were able to kill infected cells in vivo. Further analyses showed that the underlying mechanism of this reactivation crucially depended on the combinatory stimulation by TCR triggering, CD28 costimulation and Interleukin-12, both in vitro and in vivo. Our data indicates that tolerant CD8+ T cells, although initially tolerised, are still able to participate in immune surveillance. The tolerant fate of LSEC-primed CD8+ T cells is not ultimate, but rather shows a high degree of plasticity, as tolerant CD8+ T cells can be converted into effector T cells by appropriate stimulation. This could be of importance in the combat of infections by environmental pathogens which previously, due to their gastro-intestinal origin, led to LSEC-mediated tolerance.