Selective Expansion of Allogeneic Regulatory T Cells by Hepatic Stellate Cells: Role of Endotoxin and Implications for Allograft Tolerance

Abstract

Hepatic stellate cells (HSCs) may play an important role in hepatic immune regulation by producing numerous cytokines/chemokines, and expressing Ag-presenting and T cell co-regulatory molecules. Due to disruption of the endothelial barrier during cold-ischemic storage and reperfusion of liver grafts, HSCs can interact directly with cells of the immune system. Endotoxin (LPS), levels of which increase in liver diseases and transplantation, stimulates the synthesis of many mediators by HSCs. We hypothesized that LPS-stimulated HSCs might promote hepatic tolerogenicity by influencing naturally-occurring immunosuppressive CD4+CD25+FoxP3+ regulatory T cells (Tregs). Following their portal venous infusion, allogeneic CD4+ T cells, including Tregs, were found closely associated with HSCs, and this association increased in LPS-treated livers. In vitro, both unstimulated and LPS-stimulated HSCs up-regulated Fas (CD95) expression on conventional CD4+ T cells and induced their apoptosis in a Fas/FasL-dependent manner. By contrast, HSCs induced Treg proliferation, which required cell-cell contact, and was MHC class II-dependent. This effect was augmented when HSCs were pretreated with LPS. LPS increased the expression of MHC class II, CD80 and CD86, and stimulated the production of IL-1α, IL-1β, IL-6, IL-10 and TNFα by HSCs. Interestingly, production of IL-1α, IL-1β, IL-6 and TNFα was strongly inhibited, but that of IL-10 enhanced, in LPS-pretreated HSC/Treg co-cultures. Adoptively transferred allogeneic HSCs migrated to the secondary lymphoid tissues and induced Treg expansion in lymph nodes. These data implicate endotoxins-stimulated HSCs as important immune regulators in liver transplantation by inducing selective expansion of tolerance-promoting Tregs, and reducing inflammation and allo-immunity.

Stellate Cells in Hepatic Immunological Tolerance

“…An important stimulator of the synthesis of chemokines and cytokines by murine and human HSCs is LPS [50,[53][54][55][56]. Table 14.1 lists cytokines and chemokines expressed by rat HSCs and increased robustly within 1-3 h of stimulation with LPS [50].…”

Immune Responsive Gene 1 (IRG1) Promotes Endotoxin Tolerance by Increasing A20 Expression in Macrophages through Reactive Oxygen Species

“…LPS-tolerized macrophages, which are re-challenged by LPS after prior exposure to LPS, are regarded as the common model of hypo-responsiveness for SAIS (13)(14)(15). The studies showed that endotoxin tolerance reprograms TLR4 signaling with decreased proinflammatory cytokine production but increased anti-proinflammatory cytokine production by decreasing TLR4 expression, blocking tyrosine phosphorylation of TLR4 and TIRAP, TLR4-MyD88, and IRAK1-MyD88 assemblies, attenuating activation of IRAK4 and IRAK1, inhibiting K63-linked ubiquitination of IRAK1 and TRAF6, or increasing expression of negative regulators IRAK-M, SHIP-1, suppressor of cytokine signaling 1 (SOCS1), and A20 (13, 16 -18).…”

Hepatic antigen-presenting cells and regulation of liver transplant outcome

“…Recent innovative work [42,43] has extended these observations to show that HSC can regulate allogeneic T-cell responses through the PD-L1(= B7-H1)-PD-1 pathway and that HSC can protect pancreatic islet allografts from rejection by enhancing alloreactive T-cell apoptosis. More recent data [44] suggest that HSC (that interact physically with DC in hepatic sinusoids (Fig. 4)) can regulate the function of DC and promote Treg expansion, with implications for the outcome of liver transplantation.…”