A novel memory function of tolerant CD8+ T cells in anti-microbial immunity

Antigen-experienced memory T cells are defined by longevity and stem cell-like plasticity enabling them to give rise to effector T cells fighting microbial infection. It is believed that they arise from various stages of immunogenic T cell differentiation. Here, we provide evidence for a novel CD8⁺ T cell population (T_L cells) that has memory function, but is generated under non-inflammatory conditions by antigen-presenting liver sinusoidal endothelial cells (LSEC) in vitro and in vivo. After efficient cross-presentation of soluble and gut-derived antigens by LSEC to naïve CD8⁺ T cells, antigen–experienced T_L cells migrate to secondary lymphoid organs where they persist over long time in vivo. Transcriptome analysis by RNA-fingerprint revealed that T_L cells have a unique transcriptional signature distinct from naïve, effector and conventional memory T cells. Furthermore, their RNA-fingerprint differs from the signatures of T cells that undergo deletional tolerance or are rendered anergic. In contrast to memory T cells generated during infection, T_L cells lack direct cytotoxic T cell effector functions. However, in addition to an anatomical localisation reminiscent of central memory T cells, T_L cells resist deletional cross-tolerance by dendritic cells and retain a high degree of plasticity after priming by LSEC in vivo. This allows T_L cells to differentiate into protective effector T cells during viral and bacterial infections, which requires combinatorial CD28 and IL-12 signaling. Our results reveal a new pathway of memory T cell formation by liver-resident cells and will also allow deliberate exploitation of this functionally distinct cell population for vaccination.

LSEC - T cell memory - tolerance