Abstract
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−CD27hi plasmablasts or CD19+CD24hiCD27hi 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.
Highlights
Epstein–Barr virus (EBV) preferentially infects naïve B cells at oropharyngeal lymphoid tissues and subsequently establishes a persistent infection in the circulating memory B cells [1,2,3,4,5]
Besides increased levels of circulating Tfh (cTfh) cells, we observed a significant increase in the circulating Tfr (cTfr) cells during acute EBV infection (D0) in infectious mononucleosis (IM) compared to healthy individuals (HIs) (Fig. 1b, c)
We observed that both cTfr and cTfh began to decline and were significantly lower at D15 than those at D0, but Tfh at D15 were still higher than HIs (Fig. 1b, d)
Summary
Epstein–Barr virus (EBV) preferentially infects naïve B cells at oropharyngeal lymphoid tissues and subsequently establishes a persistent infection in the circulating memory B cells [1,2,3,4,5]. EBV is strongly associated with nasopharyngeal carcinoma, lymphoma and autoimmune diseases [6,7,8]. Many T cell subsets and NK are suggested to be involved in immune response to EBV infection. The mechanisms the human immune system in the control of EBV infection is not completely understood. EBV-infected infectious mononucleosis (IM) patients provide an excellent model for the study of immune responses against EBV. Follicular helper T cells (Tfh), a novel subset of C D4+ T helper cells, are essential for the formation of germinal centers (GCs) and humoral response [9]. Tfh bind to B cells via CXCR5 on the surface of Tfh and its ligand CXCL13 in the follicular GCs of B cells, migrate to B cell follicles/GCs in the lymph nodes and support B cell activation,
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