Abstract
CD4+Foxp3+ regulatory T cells (Tregs) are the main immune suppressors with subpopulation of inflamed-tissue related memory Tregs (mTregs) and non-related resting Treg (rTregs). Previously, Treg was proposed to be the cause of chronicity of hepatitis B virus (HBV) infection but with controversies. We then investigated the role of mTregs in distinct immune phases of chronic HBV infection, especially the non-inflammatory versus inflammatory phases. It was found mTregs but not rTregs increased only in the inflammatory phase and correlated with serum alanine aminotransferase (ALT) level. These mTregs accumulated in the inflamed liver, expressed significantly higher Tim-3, CCR4, CCR5 and fewer CCR7, and possessed potent suppressive function. These mTregs mainly originated from natural Tregs because of high Helios expression. Hierarchical clustering analysis showed higher frequency of mTreg was concordant with higher serum ALT and galectin-9 levels. Furthermore, galectin-9 could expand mTregs through galectin-9/Tim-3 interaction. In conclusion, increased mTregs are found only in inflammatory phase of chronic HBV infection. Galectin-9, associated with liver inflammation, contributes to the expansion of mTregs through galectin-9/Tim-3 interaction. Therefore, this expansion of mTregs only reflects as an immune regulatory mechanism to limit the on-going liver damages rather than the cause of chronicity of HBV infection.
Highlights
On the other hand, regulatory T cells (Tregs) are a specialized T cell population with the ability to suppress immune responses and maintain immunological tolerance[9]
We found that more Tregs in inflammatory phase of chronic hepatitis B virus (HBV) infection expressed C-C chemokine receptor 5 (CCR5), which was a proinflammatory chemokine receptor and indicated these Tregs possessed potential to migrate to inflammatory tissue than healthy volunteers (N vs. HBV, 4.6 ± 2.6% vs. 21.4 ± 12.7%; p < 0.001)
We show the Tregs are only increased in the IC and ENH phases but not in the IT and LR phases. It is the memory Tregs (mTregs) rather than resting Tregs (rTregs) that are responsible for this increase in Tregs. We show these mTregs with potent suppressive ability would accumulate in the inflamed liver and could be expanded through galectin-9/T-cell immunoglobin mucin 3 (Tim-3) interaction
Summary
Regulatory T cells (Tregs) are a specialized T cell population with the ability to suppress immune responses and maintain immunological tolerance[9]. The mTregs could migrate into inflamed tissue to mitigate tissue damage during the heightened responses of pro-inflammatory memory cells[16]. MTregs increased in patients with sarcoidosis[17], colon cancer[18,19,20] and hepatocellular carcinoma[18]. These mTregs, possessing pro-inflammatory chemokine receptors, could migrate to the inflammed tissue and inhibit the immune responses in inflamed tissue[18,19]. We investigate the role of Tregs in these four distinct phases of chronic HBV infection in this study, especially considering the non-inflammatory versus inflammatory phases. We study the different Tregs including rTregs and mTregs in this scenario
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