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 CTLA4cTfh2 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, CTLA4cTfh2 cells from CHB patients were ineffective in providing B cell help. Both expression of CTLA4 in cTfh and cTfh2 cells and ratios of CLTA4cTfh and CTLA4cTfh2 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.