Protective Roles of B and T Lymphocyte Attenuator in NKT Cell-Mediated Experimental Hepatitis

Abstract

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-γ upon α-glactosylceramide stimulation as compared with wild-type (WT) NKT cells. In vivo, BTLA−/− mice produced larger amounts of IL-4 and IFN-γ 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.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…[23][24][25] The humoral immune response and propensity to develop autoimmune diseases are enhanced not only in BTLA-deficient mice 23,35 but also in HVEM-deficient mice. 48 The latter strengthens the predominant in vivo function of HVEM as an inhibitory ligand rather than a costimulatory ligand.…”

“…20,22 The experimental evidence of the role of the BTLA/ HVEM pathway in humoral immunity comes from the analysis of the phenotype of BTLA-deficient mice, which revealed defects in the regulation of this branch of immunity with implications in the development of autoimmune diseases. [23][24][25] As the HVEM receptor is the unique known partner of BTLA and both molecules are expressed on T and B cells, we postulated that the HVEM/BTLA signalling pathway may participate in providing CD4 help to B cells for the production of donorspecific antibodies. 20 With this notion in mind, we set up an experimental approach to elucidate the role of this interaction in the context of the humoral immune response during the acute phase of graft rejection.…”

B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells

“…B and T lymphocyte attenuator (BTLA; CD272) is the third inhibitory coreceptor, which has been identified as an inhibitory coreceptor expressed on CD4 + T cells and B cells with similarities to CTLA-4 and PD-1 (9 ) mice have revealed that BTLA plays inhibitory roles in a variety of disease models, including experimental autoimmune encephalomyelitis (9), partially MHC-mismatched cardiac allograft (12), experimental colitis (13), and experimental hepatitis (14). We have also shown that the deficiency of BTLA spontaneously causes the breakdown of self-tolerance, resulting in the development of an autoimmune hepatitis-like disease and lymphocytic infiltration in multiple organs in aged mice (15).…”

Association between co-inhibitory molecule gene tagging single nucleotide polymorphisms and the risk of colorectal cancer in Chinese

“…Conversely, the rs2705535 TT genotype increased rectal cancer risk 84.1 % when compared to the CC + CT genotype. Additionally, the risk of rectal cancer in carriers of the TT genotype is 1.819-fold greater than that of the CC ( abe et al 2003b;Hurchla et al 2005;Murphy et al 2006;Iwata et al 2010). The inhibitory signal of BTLA appears to be mediated by the recruitment of SHP-1 and SHP-2 to two immunoreceptor tyrosine inhibitory motifs (ITIMs) in the cytoplasmic region of BTLA (Watanabe et al 2003a).…”