Infection of Epstein-Barr Virus is Associated with the Decrease of Helios+FoxP3+Regulatory T Cells in Active Ulcerative Colitis Patients

Background: Loss of immune homeostasis to enteric pathogens is considered to be involved in the pathogenesis of ulcerative colitis (UC), and regulatory T cells (Tregs) are key for this immune homeostasis. Helios exhibits an important effect on regulating the suppressive function of Tregs. Epstein-Barr virus (EBV) is more commonly detected in UC. However, whether there is an association between EBV infection and Helios(+)Tregs and its impact on disease activity of UC remain unclear. We aimed to explore the clinical significance of Helios(+)Tregs and their potential association with EBV infection in UC. Methods: Seventy-six UC patients and 38 controls were consecutively enrolled. Helios(+)FoxP3(+)Tregs were analyzed using flow cytometry and compared among groups. Eight active UC patients treated with 5-aminosalicylic acid were followed up. Correlation analyses were conducted between Helios(+)FoxP3(+)Tregs and disease activity indicators. In addition, EBV viral loads in the mucosal lesion were quantified in active UC by quantitative polymerase chain reaction and were comprehensively analyzed in subgroups of different disease severity, and their associations with Helios(+)FoxP3(+)Tregs were also analyzed. Results: Helios(+)FoxP3(+)Tregs were significantly decreased in active UC and were inversely correlated with serum C-reactive protein and Mayo score. Moreover, we observed the recovery of Helios(+)FoxP3(+)Tregs in followed-up active UC achieving remission after treatment. EBV loads were higher in active UC, and levels of Helios(+)FoxP3(+)Tregs in the EBV-positive subgroup were lower than the EBV-negative subgroup in moderate and severe active patients. Most importantly, we found that Helios(+)FoxP3(+)Tregs were significantly negatively correlated with EBV viral loads. Conclusion: Helios(+)FoxP3(+)Tregs are likely to play a pivotal role in disease activity of UC and may be influenced by EBV infection.