Antigen cross-presentation in the liver generates protective memory CD8+ T cells in the absence of inflammation

Abstract

The inflammatory context of antigen-presentation dictates the outcome of CD8+ T cell responses. Pathogen-induced inflammatory signals ensure the generation of an effector CD8+ T cell response and long-lasting T cell memory, whereas antigen-presentation in absence of inflammatory stimuli, e.g. of self-antigens, causes CD8+ T cell-deletion. The systemic distribution of antigens from certain pathogens without inflammatory stimuli therefore imposes the risk of deleting CD8+ T cells needed for anti-infectious defense. We hence wondered whether cross-presentation of exogenous antigens in the liver, the central organ for clearing soluble and gut-derived antigens, might allow for memory T cell generation even in the absence of inflammation. When restricting presentation of soluble ovalbumin to liver sinusoidal endothelial cells (LSEC), the most abundant population of liver-resident antigen-presenting cells, cross-priming by LSEC generated an antigen-experienced CD8+ T cell population that persisted long time and was insensitive to DC-mediated cross-tolerance. As LSEC-primed T cells re-expressed CD62L and relocated to secondary lymphoid organs (SLOs), a hallmark of central memory T cells (TCM), we directly compared the phenotype and in vivo distribution of both T cell populations. Clearly, LSEC-primed OT-I T cells resembled TCM induced by L. monocytogenes-OVA infection in their localization to SLOs and showed high expression of CD127, CD122 and the memory-specific transcription factor Eomes. In response to bacterial and viral infection, LSEC-primed T cells expanded and differentiated into effector T cells similar to TCM. Taken together, these data suggest that antigen-presentation under non-inflammatory conditions, if conducted by LSEC in the liver, allows for memory T cell generation. Those T cells may serve for defense against pathogens that in the first instance avoid causing inflammation.