Liver sinusoidal endothelial cells induce tolerance of autoreactive CD4+ recent thymic emigrants

The liver is a unique lymphoid organ whose microenvironment is biased towards tolerance induction. We previously found that a proportion of CD4(+) autoreactive recent thymic emigrants (RTEs) retained in the liver after thymic egress and acquired IL-10 producing capability. To investigate the tolerance of these liver persisting CD4(+) RTEs in more detail and to study the liver stromal cell types that facilitate the tolerogenic changes in young T cells, the phenotype and function of liver RTEs were further characterized and the impact of liver sinusoidal endothelial cells (LSECs) and Kupffer cells on RTEs were examined using an in vitro co-culture system. More than 70% of CD4(+) CD44(hi) RTEs in the liver acquired Foxp3(-)LAG3(+) CD49b(-) regulatory phenotype and function. But higher ratio of apoptosis with enhanced FasL and Bim expression was also found in these CD4(+) liver RTEs when compared to those in the lymph nodes and spleen. LSECs played an important role in RTEs' acquisition of tolerogenic and regulatory phenotype. These results indicate an important role of liver microenvironment in enforcing peripheral tolerance to CD4(+) thymic emigrants against self- and gut-derived antigens.