The role of CD27-CD70 signaling in myocardial infarction and cardiac remodeling.

BACKGROUND: CD4+ T cells are key players in regulating the inflammatory processes and physiological repair mechanisms engaged after acute myocardial infarction (AMI). Although signaling through the CD27-CD70 co-stimulatory pathway are known to be important in CD4+ T cell activation and proliferation in certain contexts, the role of the CD27-CD70 pathway in AMI remains unclear. METHODS AND RESULTS: A total of 43 control subjects, 42 unstable angina patients, and 90 AMI patients were enrolled in the present study. The serum levels of soluble CD27 (sCD27) in patients were measured, revealing a significant increase in serum sCD27 levels in AMI patients within 24 h of the cardiac event, after which they decreased. Correlation analyses revealed that serum sCD27 was positively correlated with cardiac troponin I (c-TnI) (r = 0.267, P = 0.011). When anti-CD70 antibody was used to block the CD27-CD70 pathway in MI model mice, we found that this treatment increased left ventricular end-diastolic dimension (LVEDD) (P < 0.01) and left ventricular end-systolic dimension (LVESD) (P < 0.01), and decreased ejection fraction (P < 0.01). Flow cytometric analysis revealed that the percentage of regulatory T cells was lower in blocking antibody-treated mice (P < 0.01), while neutrophils levels were higher (P < 0.01). The number of CD31-positive endothelial cells (P = 0.026) and α-smooth muscle actin-positive arterioles (P < 0.01) were significantly down-regulated in anti-CD70 treated-AMI mice. The formation of the extracellular matrix (ECM) was also impaired. CONCLUSION: Serum sCD27 may be a potential biomarker for AMI. Blockade of the CD27-CD70 pathway worsens cardiac dysfunction, aggravates left ventricular remodeling, and impairs scar healing after AMI, resulting in heart failure.

Effects of CD70 and CD11a in immune thrombocytopenia patients.

INTRODUCTION: CD70 and CD11a are co-stimulatory molecules that are important for the immune functions of T, B lymphocytes. Over-expressions of CD70 or CD11a cause T cell to be autoreactive. OBJECTIVES: The purpose of this study was to explore the effect of CD70 and CD11a in immune thrombocytopenia (ITP). METHODS: CD70 and CD11a mRNAs and protein expressions in CD4(+) T cells from ITP patients were measured respectively by real-time quantitative-PCR (RT-PCR) and flow cytometry. The apoptosis of T cells, B cells, and platelets in the PBMCs were analyzed by flow cytometry, and secretion of IL-4, IFN-γ, as well as IgG in the reaction supernatant were detected by ELISA. In order to investigate the effects of CD70 and CD11a over-expression on pathogenesis of ITP, anti-CD70, and anti-CD11a mAbs were used to block the signaling pathways. RESULTS: CD70 and CD11a mRNAs and protein expressions in CD4(+) T cells from ITP patients were significantly higher than healthy controls. In vitro co-culturing of PBMCs with anti-CD70 or anti-CD11a, the apoptosis of T, B lymphocytes were significantly increased but apoptosis of platelets were reduced. Anti-CD11a and anti-CD70 both significantly suppressed the secretion of IFN-γ, while anti-CD11a significantly promoted the secretion of IL-4. There was no significant difference in the healthy group. CONCLUSIONS: CD70 and CD11a facilitate the survival of T, B lymphocytes and indirectly enhance the destruction of platelets in ITP. Blockade of CD70 or CD11a are promising therapeutic approaches for ITP.

Demethylation of promoter regulatory elements contributes to CD70 overexpression in CD4+ T cells from patients with subacute cutaneous lupus erythematosus.

BACKGROUND: Impaired methylation of T-cell DNA is thought to contribute to the development of systemic lupus erythematosus (SLE). CD70 (TNFSF7) is a B-cell costimulatory molecule that contributes to excessive B-cell stimulation in vitro and in vivo. CD70 is overexpressed in CD4+ T cells of patients with SLE, and DNA demethylation occurs in promoter sequences that regulate CD70 expression in SLE CD4+ T cells. However, it is unknown whether the expression and methylation of CD70 in CD4+ T cells are affected in patients with subacute cutaneous lupus erythematosus (SCLE). OBJECTIVE: To compare CD70 expression levels and the methylation status of the CD70 promoter region in CD4+ T cells from patients with SCLE and healthy controls. METHODS: We used real-time RT-PCR to compare messenger RNA levels of CD70 and flow cytometry to compare CD70 protein levels in CD4+ T cells from patients with SCLE and healthy controls. Bisulphite sequencing was used to determine the methylation status of the CD70 promoter region. RESULTS: CD70 is overexpressed at the surface of SCLE CD4+ T cells. Demethylation of the CD70 promoter region was seen in CD4+ T cells from patients with SCLE. CONCLUSIONS: Demethylation of regulatory elements contributes to CD70 overexpression in CD4+ T cells of patients with SCLE.

Altered distribution of natural killer cell subsets identified by CD56, CD27 and CD70 in primary and chronic human immunodeficiency virus-1 infection.

Human natural killer (NK) (CD3- CD56+) cells can be divided into two functionally distinct subsets, CD3- CD56(dim) and CD3- CD56(bright). We analysed the distribution of NK cell subsets in primary and chronic human immunodeficiency virus-1 (HIV-1) infection, to determine if HIV infection stage may influence the subset distribution. In primary infection, contrary to chronic infection, the CD3- CD56(dim) subset was expanded compared to healthy controls. We also studied the effect of antiretroviral therapy administered early in infection and found that NK cell subset distribution was partially restored after 6 months of antiretroviral therapy in primary infection, but not normalized. Recently, NK cells have been divided into CD27- and CD27+ subsets with different migratory and functional capacity and CD27-mediated NK cell activation has been described in mice. We therefore investigated whether CD27 and/or CD70 (CD27 ligand) expression on NK cells, and thus the distribution of these novel NK subsets, was altered in HIV-1-infected patients. We found up-regulated expression of both CD27 and CD70 on NK cells of patients, resulting in higher proportions of CD27(high) and CD70(high) NK cells, and this phenomenon was more pronounced in chronic infection. Experiments conducted in vitro suggest that the high interleukin-7 levels found during HIV-1 infection may participate in up-regulation of CD70 on NK cell subsets. Imbalance of NK cell subsets and up-regulated expression of CD27 and CD70 initiated early in HIV-1 infection may indicate NK cell activation and intrinsic defects initiated by HIV-1 to disarm the innate immune response to the virus.

Factors involved in the generation of memory CD8+ T cells in patients with X-linked lymphoproliferative disease (XLP).

UNLABELLED: We have analysed the phenotype of T lymphocytes in two X-linked lymphoproliferative disease (XLP) patients with the same SH2D1A mutation differing in initial exposure to Epstein-Barr virus (EBV) and treatment. While memory T lymphocytes (with low CCR7 and CD62L expression) prevailed in both XLP patients, in patient 9, who developed acute infectious mononucleosis (AIM) and received B cell ablative treatment, the predominant phenotype was that of late effector CD8 T cells (CD27-, CD28-, CCR7-, CD62L-, CD45 RA+, perforin+), while in patient 4 (who did not suffer AIM) the prevalent phenotype of CD8 T lymphocytes was similar to that of normal controls (N) or to that of adult individuals who recovered from AIM: CD27+ , CD28+, CCR7-, CD62L-, CD45 RO+ and perforin-. CD57 expression (related to senescence) was also higher in CD8 T cells from patient 9 than in patient 4, AIM or N. Persistently high EBV viral load was observed in patient 9. The results obtained from this limited number of XLP patients suggest that events related to the initial EBV encounter (antigen load, treatment, cytokine environment) may have more weight than lack of SH2D1A in determining the long-term differentiation pattern of CD8 memory T cells.