T-cell-mediated inflammation of the liver. Four different types of T-helper cell responses have been described to influence various inflammatory processes in the liver. Th1 responses lead to classical activation (M1) of liver-resident macrophages such as Kupffer cells as well as recruitment of monocytes from the bloodstream, promoting a proinflammatory environment by secretion of IFNγ, TNFα, and IL-12. Th1 infiltration is mediated mainly by engagement of chemokine receptors CXCR3 and CCR5. Th2-type responses are thought to lead to an alternative activation of macrophages (M2) via IL-4 and IL-13, leading to a profibrotic response by activation of hepatic stellate cells (HSC) and inducing their differentiation into myofibroblasts. Th2-type responses are linked mainly to CCR3- and CCR4- mediated chemokine signalling as well as potentially CCR8 under certain conditions. Th17 cell responses in the liver have only recently been described to be involved in various inflammatory processes induced, for example, by alcohol-induced liver disease, HCC, or HBV/HCV-induced hepatitis. Th17 cells lead to activation of macrophages and recruitment of neutrophils, inducing an innate response by secretion of cytokines such as IL-1β, IL-6, and TNFα but also regulatory factors such as TGFβ. Recruitment of Th17 cells may be associated with CCR6- and possibly also CCR4-mediated signalling. T regulatory cells (Treg) have been described to be mainly immunosuppressive, secreting anti-inflammatory cytokines such as IL-10 and TGFβ as well as consuming IL-2, which is a key factor for immunogenic activation of T cells. Therefore, Treg inhibit and suppress T-cell activation and effector functions as well as preventing activation of innate immune cells. A broad variety of chemokine receptors have been linked to Treg migration, for example, CCR1 and CCR4 but also CCR5 as well as CCR6, suggesting a functional overlap for these receptors in different T-helper cell responses.
