Hepatitis C viraemia reversibly maintains subset of antigen‐specific T‐bet+ tissue‐like memory B cells

Background: Chronic antigen exposure and/or ageing increases the frequency of T‐box expressed in T cells (T‐bet)‐expressing B‐lymphocytes in mice. The frequency and significance of B‐cell T‐bet expression during chronic hepatitis C (HCV) infection in human subjects has never been described. Methods: Healthy controls, cirrhotic and noncirrhotic HCV‐infected patients, and non‐HCV patients with cirrhosis were recruited. Peripheral blood mononuclear cells were phenotyped for expression of T‐bet and related markers by flow cytometry. In a subset of patients who underwent antiviral therapy and were cured of HCV infection (sustained virological response), the dynamics of T‐bet expression in B cells was monitored. After cure, convalescent B cells were tested for T‐bet expression after re‐exposure to infected plasma or recombinant HCV proteins. Results: Forty‐nine patients including 11 healthy donors, 30 hepatitis C‐infected individuals (nine with liver cancer, 13 with cirrhosis, eight without cirrhosis) and eight patients with cirrhosis due to non‐HCV‐related cause were recruited. We found that B cells in patients with chronic HCV exhibited increased frequency of T‐bet+ B cells relative to noninfected individuals (median 11.5% v. 2.2%, P<.0001) but that there were no significant differences between noncirrhotic, cirrhotic and cancer‐bearing infected individuals. T‐Bet⁺ B cells expressed higher levels of CD95, CXCR3, CD11c, CD267 and FcRL5 compared to T‐bet^? B cells and predominantly exhibit a tissue‐like memory CD27^?CD21^? phenotype independent of HCV infection. T‐bet⁺ B cells in HCV‐infected patients were more frequently class‐switched IgD^?IgG⁺ (40.4% vs. 26.4%, P=.012). Resolution of HCV infection with direct‐acting antiviral (DAA) therapy leads to a marked reduction in the frequency of T‐bet⁺ B cells (median 14.1% pretreatment v. 6.7% end of treatment v. 6.1% SVR12, P≤.01). Re‐exposure of convalescent (cured) B cells to viremic plasma and recombinant HCV E2 protein led to re‐expression of T‐bet. Conclusion: Chronic antigenemia in chronic HCV infection induces and maintains an antigen‐specific T‐bet⁺ B cell. These B cells share markers with tissue‐like memory B cells. Antigen‐driven T‐bet expression may be a critical suppressor of B‐cell activation in chronic HCV infection.     

T-bet is essential for the progression of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is mediated by myelin-specific CD4+ T helper 1 (Th1) cells, while recovery from the disease is associated with the presence of Th2 cells. Here we used animals with targeted deletion of the T-bet gene to determine its role in the progression of EAE. T-bet regulates the production of interferon-gamma (IFN-gamma) in CD4+ and natural killer cells, and CD4+ T cells from T-bet-deficient mice were unable to differentiate into a Th1 phenotype. Moreover BALB/c mice deficient in T-bet were resistant to the induction of EAE disease, with minimal inflammatory infiltrates in the central nervous system. These mice were resistant to EAE induction even when PLP(180-199) peptide specific effector T cells from BALB/c wild type were transferred to BALB/c T-bet-deficient mice. This resistance to EAE is may be caused by the production of the anti-inflammatory cytokine interleukin-10 (IL-10) from the spleen cells upon ex vivo stimulation with PLP(180-199) peptide and in vivo presence in the central nervous system. There was no difference in the recall responses in spleen cells from T-bet-deficient and wild type mice; however, less secretion of IFN-gamma was observed from primed splenocytes. The expression of IFN-gamma was less in the central nervous system of T-bet-deficient mice whereas IL-10 was significantly higher in T-bet-deficient as compared to wild type mice. These data indicate that T-bet genes play a critical role in maintaining the encephalitogenic nature of CD4+ T cells in autoimmune responses during EAE disease progression.     

从TH1/TH2细胞平衡角度探讨清肺口服液对感染RSV小鼠内T-bet、GATA3水平的影响

目的:从TH1/TH2细胞平衡角度观察清肺口服液对感染RSV肺炎小鼠肺组织内T-bet、GATA3及IL-12的影响,并对其作用机制进行初步探讨。方法:将45只BABL/c小鼠随机分为5组,正常对照组,模型组,利巴韦林组,清肺(3.4 g/mL)组,清肺(10.2 g/mL)组。每组9只,用RSV(Long株)病毒予小鼠滴鼻造模,病毒激发24 h后,分给药72 h后处死小鼠,立即取小鼠肺组织行病理分析,及肺细胞中RT-PCR检测T-bet和GATA3蛋白表达水平,ELISA方法检测肺泡灌洗液(BALF)中IL-12的含量,流式细胞术方法检测小鼠脾脏细胞IL-4和INF-γ表达含量。结果:小鼠模型组与各给药组小鼠肺组织均有T-bet和IL-12(P<0.05,P<0.01)显著升高,GATA3显著降低。结论:清肺口服液具有调节TH1/TH2平衡,并对于感染rsv小鼠体内T-bet及IL-12细胞因子具有明显提升作用,而对GATA3则有明显抑制效果,从而进一步证明了清肺口服液治疗RSV病毒性肺炎有效性。