Induction of cytokine production in naive CD4⁺ T cells by antigen- presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward T(h1) cells

Background and Aims: 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. Methods: 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. Results: 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. Conclusions: 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.