Protective roles of B and T lymphocyte attenuator in NKT cell-mediated experimental hepatitis

Although B and T lymphocyte attenuator (BTLA) was originally identified as an inhibitory coreceptor selectively expressed on Th1 cells and B cells, recent studies have revealed that BTLA is expressed on a variety of cells, including macrophages, dendritic cells, and NK cells, and modulates their functions. However, the role of BTLA in the regulation of NKT cell function remains unknown. In this study, we found that BTLA was expressed on NKT cells at the levels similar to those on T cells and that BTLA-deficient (BTLA(-/-)) NKT cells produced larger amounts of IL-4 and IFN-gamma upon alpha-glactosylceramide stimulation as compared with wild-type (WT) NKT cells. In vivo, BTLA(-/-) mice produced larger amounts of IL-4 and IFN-gamma upon Con A injection and were more susceptible to Con A-induced hepatitis than WT mice. In addition, the augmentation of Con A-induced hepatitis in BTLA(-/-) mice was not observed in BTLA/NKT-double deficient mice. Moreover, NKT(-/-) mice reconstituted with BTLA(-/-) NKT cells were significantly more susceptible to Con A-induced hepatitis as compared with NKT (-/-) mice reconstituted with WT NKT cells. These results suggest that BTLA functions as the inhibitory coreceptor of NKT cells and plays a critical role in the prevention of NKT cell-mediated liver injury.