CTLA4 + CD4 + CXCR5 - FOXP3 + T cells associate with unfavorable outcome in patients with chronic HBV infection

Abstract

Abstract Background Recently, a new subset of CD4+FOXP3+cells expressing CXCR5, which exhibits a unique phenotype and function, has been identified in viral infections. In contrast, the role of CD4+CXCR5−FOXP3+ T cells in patients with chronic HBV infection remains unclear. Methods Treatment-naïve chronic HBV-infected patients, HBV-related hepatic failure, and a longitudinal cohort of chronic hepatitis B (CHB) patients with nucleos(t)ide analogue treatment were enrolled for analysis of CD4+CXCR5−FOXP3+ T cell responses. Results Single-cell RNA sequencing (scRNA-seq) revealed that circulating CD4+CXCR5−FOXP3+ T cells presented distinct inhibitory features compared to spleen tissue. Meanwhile, patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure showed an upregulation of immune-suppressive features (PD-1, CTLA4, GITR) on CD4+CXCR5−FOXP3+T cells; in vitro analysis found HBeAg and HBcAg stimulation led to elevated levels of inhibitory molecules. Notably, the frequency of CTLA4+CD4+CXCR5−FOXP3+ T cells was positively correlated with HBV DNA levels, and longitudinal analysis demonstrated a high frequency of this subset at 12 weeks of antiviral treatment predicted unfavorable outcome in CHB patients. Conclusions The CTLA4+CD4+CXCR5FOXP3+ T cells, regulated by HBV antigens, are related to unfavorable outcomes in HBV-infected patients; these data indicated that alleviating CTLA4+CD4+CXCR5FOXP3+ T cells may improve the prognosis of HBV infection.