Murine liver sinusoidal endothelial cells (LSECs) constitutively express accessory molecules and can present antigen to memory T_h1 CD4⁺ T cells. Using a T-cell receptor transgenic mouse line, we addressed the question whether LSECs can prime naive CD4⁺ T cells.

Purified LSECs were investigated for their ability to induce activation and differentiation of naive CD4⁺ T cells in comparison with bone marrow–derived antigen-presenting cells and macrovascular endothelial cells. Activation of T cells was determined by cytokine production. LSECs were further studied for expression of interleukin (IL)-12 by reverse-transcription polymerase chain reaction, and the unique phenotype of LSECs was determined by flow cytometry.

We provide evidence that antigen-presenting LSECs can activate naive CD62L^high CD4⁺ T cells. Activation of naive CD4⁺ T cells by LSECs occurred in the absence of IL-12. In contrast, macrovascular endothelial cells from aorta could not activate naive CD4⁺ T cells. The unique functional characteristics of microvascular LSECs together with a unique phenotype (CD4⁺, CD11b⁺, CD11c⁺, CD80⁺, CD86⁺) make these cells different from macrovascular endothelial cells. Furthermore, LSECs did not require in vitro maturation to activate naive CD4⁺ T cells. Most importantly, LSECs failed to induce differentiation toward T_h1 cells, whereas conventional antigen-presenting cell populations induced a T_h1 phenotype in activated CD4⁺ T cells. Upon restimulation, CD4⁺ T cells, which were primed by antigen-presenting LSECs, expressed interferon gamma, IL-4, and IL-10, which is consistent with a T_h0 phenotype. Exogenous cytokines (IL-1β, IL-12, or IL-18) present during T-cell priming by antigen-presenting LSECs could not induce a T_h1 phenotype, but neutralization of endogenously produced IL-4 during T-cell priming led to a reduced expression of IL-4 and IL-10 by CD4⁺ T cells upon restimulation. The addition of spleen cells to cocultures of LSECs and naive CD4⁺ T cells during T-cell priming led to differentiation of T cells toward a T_h1 phenotype.

The ability of antigen-presenting LSECs to induce cytokine expression in naive CD4⁺ T cells and their failure to induce differentiation toward a T_h1 phenotype may contribute to the unique hepatic microenvironment that is known to promote tolerance. GASTROENTEROLOGY 1999;116:1428-1440