Altered ratio of circulating follicular regulatory T cells and follicular helper T cells during primary EBV infection

Follicular help T cells (Tfh) play an important role in the activation and differentiation of B cells, while follicular regulatory T cells (Tfr) control Tfh and resulting humoral immune responses. Accumulating evidence has demonstrated that the dysregulation of Tfr contributed to the pathogenesis of infectious diseases. However, the role of Tfr in Epstein–Barr virus (EBV) infection remains lacking. Fifty-five EBV-infected infectious mononucleosis (IM) patients and 21 healthy individuals (HIs) were recruited in the study. We investigated the number of Tfr (FoxP3⁺CXCR5⁺PD-1⁺CD4⁺) and Tfh (FoxP3⁻CXCR5⁺PD-1⁺CD4⁺) of peripheral blood in IM patients at diagnosis (D0) and day 15 after diagnosis (D15) via multicolor flow cytometry. Results revealed that circulating Tfh (cTfh) and Tfr (cTfr) of IM at D0 were both increased compared to HIs, and cTfr began to decline and return to normal at D15, while cTfh was still higher than those of HIs. More interestingly, the cTfr/cTfh ratio of IM at D0 and D15 was lower than that of HIs, suggesting that the balance between cTfh and cTfr was disturbed during primary EBV infection. Correlation analysis showed a positive correlation between cTfr with CD19⁺IgD⁺CD27⁻ naive B cells, CD19⁺IgD⁻CD27^hi plasmablasts or CD19⁺CD24^hiCD27^hi B cells. Moreover, both cTfr and the cTfr/cTfh ratio of IM at D0 were negatively correlated with EBV DNA virus load. These results indicate that an imbalance of cTfr and cTfh cells may be involved in the immunopathogenesis of EBV-infected IM patients and may provide novel strategies for controlling EBV-related disease.