Induction of cytokine production in naive CD4+ T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells

Background & 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-1 beta, 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 Th1 phenotype may contribute to the unique hepatic microenvironment that is known to promote tolerance.