Which cells are APC

Modulation of CD4 + T cells by professional and non-professional antigen presenting cells of the liver

In regulating the immune response, the liver is known for its tolerogenic potential. In particular, liver sinus endothelial cells (LSEC), a population of non-professional antigen presenting cells (APC) that line the sinusoid lumen, contribute to tolerance induction. LSEC-activated CD4 + T cells do not express any proinflammatory cytokines and show a strong expression of the intestinal homing molecules α4β7 integrin and CCR9. CD4 + T cells circulating through the liver sinusoids not only interact with LSEC, but are also activated by professional liver APC (LAPC), which is composed of macrophages, dendritic cells, and B cells. Therefore, in vitro cultures were used to investigate what proportion the various APC populations have in the CD4 + T cell response in the liver and what mechanisms underlie the phenotype of hepatically activated CD4 + T cells. Compared to LSEC-activated CD4 + T cells, LAPC-activated CD4 + T cells express a lot of IFNγ, little α4β7 integrin and similar amounts of P-Lig, a homing receptor for the skin and inflamed tissue. The presence of additional LSEC during activation of CD4 + T cells by LAPC increased expression of α4β7 integrin and reduced IFNγ expression. The blockade of the retinoic acid signaling showed an inhibition of the expression of α4β7 integrin and led to an increase in the expression of IFNγ and P-Lig in liver-activated CD4 + T cells. A strong costimulatory signal from the addition of an anti-CD28 antibody or a strong T-cell activation reduced the LSEC-induced α4β7 integrin expression, while the expression of IFNγ and P-Lig increased. These results show that in hepatically activated CD4 + T cells the provision of retinoic acid and the low expression of the costimulatory molecules by LSEC induce migration into the intestine and reduce the expression of the proinflammatory cytokine IFNγ. It should be noted that despite optimal co-stimulation and blockade of retinoic acid signaling, LSEC-activated CD4 + T cells express only small amounts of IFNγ. Presumably, the lack of Th-1-inducing factors such as IL-12 is responsible for the lack of Th-1 cell induction by LSEC. In summary, the provision of retinoic acid and the weak activation and co-stimulation by LSEC were identified as mechanisms underlying the different phenotype of LSEC- and LAPC-activated CD4 + T cells. While the additional presence of LAPC compensates for the weak activation and co-stimulation by LSEC, retinoic acid signaling is an active mechanism that regulates the expression of α4β7 integrin, P-Lig and IFNγ in hepatically activated CD4 + T cells.


In the regulation of immune responses the liver usually promotes tolerance rather than immunity. In particular, liver sinusoidal endothelial cells (LSEC), a population of hepatic non-professional antigen-presenting cells (APC) that line the liver sinusoids, shift T-cell responses towards tolerance. LSEC-activated CD4 + T cells do not express pro-inflammatory cytokines such as IFNγ and are characterized by the expression of the gut-homing molecules α4β7 integrin and CCR9. In the sinusoids, circulating CD4 + T cells are not only activated by LSEC but also interact with professional hepatic APC (LAPC), comprised of dendritic cells, macrophages and B cells. Therefore in the present study we investigated, the relative contributions of hepatic non-professional and professional APC to the development of CD4 + T-cell responses by using in vitro co-culture systems. Furthermore, underlying mechanisms responsible for the described phenotype of liver-activated CD4 + T cells were analyzed. In comparison to LSEC-activated CD4 + T cells, LAPC-activated CD4 + T cells expressed high amounts of IFNγ, low levels of α4β7 integrin and similar level of P-Lig, a homing receptor for skin and inflammatory tissue. The presence of LSEC during CD4 + T cell activation by LAPC enhanced α4β7 integrin expression and reduced IFNγ production. Blockage of retinoic acid signaling inhibited α4β7 integrin expression and increased expression of IFNγ and P-Lig in liver-activated CD4 + T cells. Also a strong co-stimulatory signaling through an anti-CD28 antibody or strong T cell activation reduced the LSEC-mediated expression of α4β7 integrin while expression of IFNγ and P-Lig was increased. These findings indicate that the provision of retinoic acid as well as the weak level of co-stimulation by LSEC is involved in the regulation of gut-homing receptors and IFNγ expression in hepatic-activated CD4 + T cells. Importantly, despite optimal stimulatory conditions and blockage of retinoic acid signaling LSEC induced only small levels of IFNγ in CD4 + T cells, suggesting that a lack of Th1-inducing factors such as IL-12 is responsible for the failure of Th1 induction on LSEC-activated CD4 + T cells. In summary, the provision of retinoic acid as well as the LSEC-mediated lack of activation and co-stimulation belong to the mechanisms which resulting the different phenotype of LSEC- and LAPC-activated CD4 + T cells. Whereas the lack of activation and co-stimulation of LSEC-activated CD4 + T cells is balanced by the additional presence of LAPC, the provision of retinoic acid is an active mechanism, which regulates the expression of α4β7 integrin, P-Lig and IFNγ in liver -activated CD4 + T cells.