PD-1 Expressing CD8+CXCR5+ Follicular T Cells Constitute Effector Rather Than Exhaustive Phenotype in Patients with Chronic Hepatitis B.

Classical CD8 T cells are implicated for protective and pathogenic roles in chronic hepatitis B(CHB) infection. Recently, a new subset of CD8 T cells expressing CXCR5 and exhibiting features of TFH cells has been identified during chronic viral infections. However, in CHB, their roles have not yet been well defined. We characterized circulating CD8+CXCR5+/- cells and investigated their association with clinical and viral factors. We found that CHB infection did not influence the overall frequencies of CD8+CXCR5+ cells while CD8+CXCR5- cells were increased. However, among CHB, CD8+CXCR5+ cells were higher in patients with low HBsAg and HBV DNA levels, patients who were HBeAg-negative and had high fibrosis scores, and exhibited significant association with HBsAg and HBV DNA reduction. Contrarily, CD8+CXCR5- cells were expanded and positively correlated with patients having high HBsAg, HBV DNA and ALT levels. CD8+CXCR5+ cells express co-stimulatory molecules ICOS, OX40, CD40L, inhibitory molecule PD-1, transcription factors, BCL-2, BCL-6 and STAT3, and are enriched in effector and central memory phenotype. Moreover, these cells are heterogeneous in nature as they constitute different subsets of cytotoxic follicular T cells (TCF) including TCF1, TCF2, TCF17 and TCF22. Despite expressing high PD-1, CD8+CXCR5+ cells are activated, proliferating, secreting more IFN-γ, IL-21 and IL-22, and have better cytolytic potential than CD8+CXCR5- cells, which inhibited post PD-1/PD-L1 blockade. CD8+CXCR5+ cells are efficient in helping B cells in terms of plasmablasts and plasma cell generation. In conclusion, CD8+CXCR5+ cells are enriched in effector phenotypes, produce HBV-specific cytokines despite increased PD-1 and are associated with HBsAg and HBV DNA reduction. These cells competently support B cell function, required for viral clearance, which may serve them as potential therapeutic targets for CHB.