Restoring homeostasis of CD4+ T cells in hepatitis-B-virus-related liver fibrosis

Table 1 Role of Treg and Th17 cell-related interleukins in chronic hepatitis

Treg and Th17-related interleukins	Cellular sources	Roles in CD4+ T cell differentiation and function	Roles in liver inflammation and fibrosis	Ref.
IL-17	Th17, neutrophils, NKT cells, macrophages, γδT cells	Characteristic cytokine of Th17 cells: pro-inflammatory	Pro-inflammatory	[6-8,10,31]
			Pro-fibrotic
IL-21	Th17, Tfh, NKT cells	Promotes differentiation of Th17 cells;	Promotes HBV-related liver injury and fibrogenesis	[18,21,28-30]
		Inhibits differentiation of Treg cells
IL-23	DCs, macrophages	Promotes Th17 cell proliferation and stabilizes effector Th17 cells	Promotes HBV-related liver injury	[22,80]
IL-22	Th17, Th22, activated NK and NKT cells	Characteristic cytokine of Th22 cells: pro-inflammatory	Hepatoprotective? Pro-inflammatory? Pro-fibrotic? Anti-fibrotic?	[23,24,26,27]
IL-10	Treg, hepatocytes, Kupffer cells, LSECs, HSCs, Breg	Inhibits Th1, Th2, Th17 cell differentiation and cytokine production	Anti-inflammatory	[35,38,81]
			Anti-fibrotic
IL-35	Treg, Breg	Immunosuppressive	Anti-inflammatory	[30,31,33,34]
			Anti-fibrotic?
IL-33	LSECs, activated HSCs	Promotes Th2 differentiation and cytokine production;Increases Treg cells?Activates Tfh cells?	Pro-fibrotic	[86-88,90,91]
			Anti-inflammatory?

Treg: Regulatory T cells; Tfh: T follicular helper cells; HBV: Hepatitis B virus; NK: Natural killer cells; NKT: Natural killer T cells; DCs: Dendritic cells; Breg: Regulatory B cells; LSECs: Liver sinusoidal endothelial cells; HSCs: Hepatic stellate cells.

Table 2 Role of surface molecules in chronic hepatitis

Surface molecules	Expression on T cells and CD4+ T cell subsets	General effects	Role in liver inflammation and fibrosis	CD4+ T cell response to blocking	Ref.
PD-1	CD8+ T cells	Inhibits T cell activation;	Causes exhaustion of HBV-specific CD8+ and CD4+ T cells	Partially-revived proliferation and function	[96-98,104]
	CD4+ T cells	Maintains tolerance
TIM-3	CD8+ T cells	Inhibits T cell activation; Maintains tolerance	Promotes progression of HBV infection	Revived more (blocked with PD-1)	[99,100,102-104]
	CD4+ T cells
	Treg cells
CTLA-4	Activated CD4+ T cells	Inhibits CD4+ T cell over-activation;	Promotes persistence of HBV and progression of HBV infection	Unknown	[105,107,109,110]
	Treg cells	Maintains tolerance
CB2	CD4+ T cells	Immunoregulatory: pro-inflammatory or anti-inflammatory; Anti-fibrotic	Anti-inflammatory;Anti-fibrotic;Hepatoprotective?	Decreased frequency and function of Th17 cells	[112-114]
	CD8+ T cells
	Th17 cells

PD-1: Programmed cell-death protein 1; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; TIM-3: T-cell immunoglobulin domain and mucin domain-containing molecule 3; CB2: Cannabinoid receptor 2; HBV: Hepatitis B virus.