Circulating Th2-biased T follicular helper cells impede antiviral humoral responses during chronic hepatitis B infection through upregulating CTLA4

Failure in curing chronic hepatitis B (CHB) caused by hepatitis B virus (HBV) can lead to functional impairment of B cells. Cytotoxic T-lymphocyte associated antigen 4 (CTLA4) regulates B cell and T follicular helper (Tfh) cell differentiation. In addition, Tfh cells play a critical role in helping B cells generate antibodies upon pathogen exposure. Here, we analyzed the global and HBsAg-specific B cells and circulating Tfh (cTfh) cells using samples from treatment-naïve and Peg-IFN-α-treated CHB patients and healthy subjects. Compared to healthy subjects, CTLA4 expression was significantly increased in cTfh cells, from CHB patients. The frequency of CTLA4+cTfh2 cells was negatively correlated with that of HBsAg-specific resting memory B cells. Importantly, inhibition of CTLA4 restored HBsAb secretion and promoted plasma cell differentiation. In addition, CTLA4+cTfh2 cells from CHB patients were ineffective in providing B cell help. Both expression of CTLA4 in cTfh and cTfh2 cells and ratios of CLTA4+cTfh and CTLA4+cTfh2 cells were significantly decreased in Peg-IFN-α-treated CHB patients who showed complete responses. Thus, our results highlighted that cTh2-biased T follicular helper cells could impede antiviral humoral responses during chronic HBV infection by upregulating CTLA4, suggesting that further optimizing potent Tfh cell responses may promote functional cure of CHB.