B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy.
ABSTRACT In an effort to identify immunoregulatory molecules on dendritic cells (DC), we generated and screened for mAbs capable of modulating the T cell stimulatory function of DC. A particularly interesting mAb was mAb DF272. It recognizes monocyte-derived DC, but not blood monocytes or lymphocytes, and has profound immunomodulatory effects on DC. Treatment of DC with intact IgG or Fab of mAb DF272 enhanced their T cell stimulatory capacity. This effect on DC was accompanied by neither an up-regulation of costimulatory molecules such as B7.1 (CD80), B7.2 (CD86), and MHC class II molecules nor by an induction of cytokine production, including IL-1, TNF-alpha, IL-10, and IL-12. Moreover, the well-established inhibitory function of IL-10-treated DC could be reverted with mAb DF272. Even T cells, anergized because of stimulation with IL-10-treated DC, could be reactivated and induced to proliferate upon stimulation with mAb DF272-treated DC. Furthermore, mAb DF272-treated DC favored the induction of a type-1 cytokine response in T cells and inhibited IL-10 production. By using a retrovirus-based cDNA expression library generated from DC, we cloned and sequenced the mAb DF272-defined cell surface receptor and could demonstrate that it is identical with B7-H1 (programmed death-1 ligand), a recently identified new member of the B7 family of costimulatory molecules. Our results thus demonstrate that the mAb DF272-defined surface molecule B7-H1 represents a unique receptor structure on DC that might play a role in the induction and maintenance of T cell anergy.
Article: Longitudinal fluctuations in PD1 and PD-L1 expression in association with changes in anti-viral immune response in chronic hepatitis B.[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Controversy exists regarding the role of PD1 and its ligand PD-L1 in chronic hepatitis B infection. In some studies, persistent HBV infection has been attributed to high levels of PD-1 and PD-L1 expression on HBV-specific T-cells and antigen-presenting cells (APCs) respectively. Other studies revealed that the up-regulation of PD-1 and PD-L1 during an acute inflammation phase is required to offset increasing positive co-stimulatory signals to avoid severe damage by an over-vigorous immune response. METHODS: Fifteen chronic hepatitis B patients, with inflammatory flare episode, were recruited prospectively. Based on serum HBV-DNA, HBsAg load, and ALT values, inflammatory flare episode were divided into initial, climax, decline and regression phase. Blood sample and liver biopsy tissues from each individual were taken in these 4 phases respectively. Circulating and intra-hepatic PD1 and PD-L1 expression levels were monitored throughout the inflammatory flare episode by flow cytometry and immunostaining and these expression levels were related to the HBV-specific T-cell changes, expression of pro-inflammatory cytokines, HBV-DNA replication and HBV antigen load. RESULTS: ]The levels of PD-1 and PD-L1 expressions were significantly up-regulated in the inflammation ascending phase, initial and climax period and in parallel with HBV-specific colon expansion. It showed increasing the level of serum ALT and decreasing the HBV-DNA loads. As the level of inflammation reduced, the circulating and intra-hepatic PD1 and circulating PD-L1 decreased progressively in concordance with serum ALT, HBV-DNA and HBsAg loads decreased except intra-hepatic PD-1 expression. Intra-hepatic PD-L1 expression did not decrease significantly during the regression phase of inflammation compared to that in prior period. The intra-hepatic PD-L1 expression remained relatively on higher level when serum HBV-DNA load and ALT decreased to approximately normal range. CONCLUSION: The relatively high level of intra-hepatic PD-L1 expression during the inflammatory regression period may contribute to constitute an immunosuppressive microenvironment, which facilitate persistent HBV infection via the inhibition of HBV-specific T cell clonal expansion.BMC Gastroenterology 08/2012; 12(1):109. · 2.42 Impact Factor
Article: Hepatic stellate cells promote immunotolerance following orthotopic liver transplantation in rats via induction of T cell apoptosis and regulation of Th2/Th3-like cell cytokine production.[show abstract] [hide abstract]
ABSTRACT: Hepatic stellate cells (HSCs) have been demonstrated to have immunoinhibitory activity. The aim of this study was to investigate the role of HSCs in the development of immunotolerance following liver transplantation. A rat liver transplantation tolerance model [donor Lewis into recipient Dark Agouti (DA)] and rejection (donor DA into recipient Lewis) was established. On the 7th day following transplantation, the HSCs and T cells were isolated from the rats of either the tolerance or rejection group and cultured together. The apoptosis rate of the T cells was determined 24 h later by flow cytometry following staining with anti-CD3 mAb and Annexin V-FITC/PI. Additionally, the FasL expression of HSCs was determined by flow cytometry following staining with anti-FasL mAb. The protein levels of IL-2, TNF-α, TGF-β and IL-10 in the supernatant collected from mixed lymphocyte reaction cultures of HSCs and T cells for 5 days were measured using ELISA assays. HSCs isolated from the tolerance group had a higher T-cell apoptosis induction activity compared with those of the rejection group. The activity of the HSCs was partially reversed by FasL blocking mAb. Accordingly, the FasL expression level of HSCs in the tolerance group was revealed to be higher than that of the rejection group. Moreover, HSCs stimulated IL-10 and TGF-β production in the tolerance group. This study suggests that HSCs are involved in liver transplantation immune tolerance via the induction of T-cell apoptosis partially mediated by the Fas/FasL pathway and the activation of Th2/Th3-like cell cytokine production.Experimental and therapeutic medicine 01/2013; 5(1):165-169.
Article: Age-Related Patterns in Human Myeloid Dendritic Cell Populations in People Exposed to Schistosoma haematobium Infection.[show abstract] [hide abstract]
ABSTRACT: Urogenital schistosomiasis is caused by the helminth parasite Schistosoma haematobium. In high transmission areas, children acquire schistosome infection early in life with infection levels peaking in early childhood and subsequently declining in late childhood. This age-related infection profile is thought to result from the gradual development of protective acquired immunity. Age-related differences in schistosome-specific humoral and cellular responses have been reported from several field studies. However there has not yet been a systematic study of the age-related changes in human dendritic cells, the drivers of T cell polarisation. Peripheral blood mononuclear cells were obtained from a cohort of 61 Zimbabwean aged 5-45 years with a S. haematobium prevalence of 47.5%. Two subsets of dendritic cells, myeloid and plasmacytoid dentritic cells (mDCs and pDCs), were analyzed by flow cytometry. In this population, schistosome infection levels peaked in the youngest age group (5-9 years), and declined in late childhood and adulthood (10+ years). The proportions of both mDCs and pDCs varied with age. However, for mDCs the age profile depended on host infection status. In the youngest age group infected people had enhanced proportions of mDCs as well as lower levels of HLA-DR on mDCs than un-infected people. In the older age groups (10-13 and 14-45 years) infected people had lower proportions of mDCs compared to un-infected individuals, but no infection status-related differences were observed in their levels of HLA-DR. Moreover mDC proportions correlated with levels of schistosome-specific IgG, which can be associated with protective immunity. In contrast proportions of pDCs varied with host age, but not with infection status. Our results show that dendritic cell proportions and activation in a human population living in schistosome-endemic areas vary with host age reflecting differences in cumulative history of exposure to schistosome infection.PLoS Neglected Tropical Diseases 09/2012; 6(9):e1824. · 4.69 Impact Factor