Response to Zhang et al . re:“CXCR5 + CD8 + T Cells Indirectly Offer B Cell Help and Are Inversely Correlated with Viral Load in Chronic Hepatitis B Infection”

Dear Editor,

After the discovery that the CXCR5⁺CD8⁺ T cells exhibited more potent cytotoxicity than the CXCR5⁻CD8⁺ T cells in chronic lymphocytic choriomeningitis virus-infected mice, growing interest has been generated around the function of this particular CD8⁺ T cell subset in a variety of human diseases, which includes chronic hepatitis B (CHB) infection, a disease currently affecting millions of individuals worldwide. Works from Zhang et al. (2018) and our own group have both investigated the characteristics of CXCR5⁺CD8⁺ T cells in CHB patients, “CXCR5⁺ CD8⁺ T Cells Indirectly Offer B Cell Help and Are Inversely Correlated with Viral Load in Chronic Hepatitis B Infection” (Jiang et al., 2017). We showed that the untreated CHB patients presented significantly elevated frequencies of CXCR5⁺CD8⁺ T cells than healthy controls. These CXCR5⁺CD8⁺ T cells presented an indirect role in promoting B cell responses. Zhang et al. complemented our results by examining the CXCR5⁺CD8⁺ T cells in treated CHB patients, and they found no difference in frequency between treated CHB patients and healthy controls. Contrasting these results, it appears that antiviral medication might mediate a restoration effect on the immune system. It would, therefore, be interesting to examine for how long these treated CHB patients have been on antivirals for the immune system to restore to the control state.

In contrast, Zhang et al. also uncovered some differences between the CXCR5⁺CD8⁺ T cells in treated CHB patients and those in healthy controls. They observed an upregulation in PD-1 and Tim-3 expression on CXCR5⁺CD8⁺ T cells from treated CHB patients, compared with those from healthy controls. PD-1 and Tim-3 have been shown to demarcate functionally exhausted CD8⁺ T cells in chronic virus infections. The fact that CXCR5⁺CD8⁺ T cells overexpressed PD-1 and Tim-3 would suggest that they might have impaired effector function. However, Zhang et al. later compared the levels of granzyme B, IFN-gamma, and TNF-alpha expression in Phorbol 12-Myristate 13-Acetate/ionomycin-stimulated CXCR5⁺CD8⁺ T cells from CHB patients and from healthy controls, and found no difference between the two. It is, therefore, interesting to examine whether PD-1 and Tim-3 in CXCR5⁺CD8⁺ T cells have different effects from PD-1 and Tim-3 in CXCR5^-CD8⁺ T cells. In the future, it might be attempted to further fractionate total CXCR5⁺CD8⁺ T cells into PD-1⁺, Tim-3⁺, and PD-1⁺Tim-3⁺ subsets, and the effector functions of each should be examined.