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 & Aims: Murine liver sinusoidal endothelial cells (LSECs) consti tutively express accessory molecules and can present antigen to memory T-h1 CD4(+) T cells. Using a T-cell receptor transgenic mouse line, we addresse d the question whether LSECs can prime naive CD4(+) T cells. Methods: Purif ied LSECs were investigated for their ability to induce activation and diff erentiation 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 c hain reaction, and the unique phenotype of LSECs was determined by flow cyt ometry. Results: We provide evidence that antigen-presenting LSECs can acti vate naive CD62L(high) CD4(+) T cells. Activation of naive CD4(+) T cells b y LSECs occurred in the absence of IL-12. In contrast, macrovascular endoth elial cells from aorta could not activate naive CD4(+) T cells. The unique functional characteristics of microvascular LSECs together with a unique ph enotype (CD4(+), CD11b(+), CD11c(+), CD80(+), CD86(+)) make these cells dif ferent from macrovascular endothelial cells. Furthermore, LSECs did not req uire in vitro maturation to activate naive CD4(+) T cells. Most importantly , LSECs failed to induce differentiation toward T-h1 cells, whereas convent ional antigen-presenting cell populations induced a T-h1 phenotype in activ ated CD4+ T cells. Upon restimulation, CD4+ T cells, which were primed by a ntigen-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 I L-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 differentiati on 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 contribu te to the unique hepatic microenvironment that is known to promote toleranc e.