TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients with Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4 + T cell response to liver Ags. However, the pathogenic function of CD4 + effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4 + T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4 + T cells producing IFN-g or IL-17. In AIH, TNF-producing CD4 + T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4 + T cells were not. However, the majority of the TNF-producing CD4 + T cells in AIH also produced IFN-g, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4 + T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4 + T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH.

Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver

“…The liver-infiltrating CD4 + T cells in Alb-iGP_Smarta mice were dominated by Th1 cells producing IFN-γ (37.5%, Figure 3E; P = 0.0012), which were significantly increased as compared with Alb-iGP control mice (8.6%). Interestingly, and in accordance with our recent findings in human AIH (36), the liver-infiltrating Th1 cells in Alb-iGP_Smarta mice were marked by coproduction of IFN-γ and TNF in liver (Figure 3F and Supplemental Figure 2B; P = 0.0012), indicating potent inflammatory activation. The fraction of IL-17 producers among the intrahepatic CD4 + T cells was also elevated in Alb-iGP_Smarta mice (14.8 vs. 2.2% in Alb-iGP controls; Figure 3G; P = 0.0003).…”

“…Accordingly, the pathogenic activation of GP-reactive CD4 + T cells in mice was marked by coproduction of the classical Th1 cytokines IFN-γ and TNF (Figure 3F). Of note, we found a similar dominance of IFN-γ and TNF coproducers among the liver-infiltrating CD4 + T cells in human AIH (36), indicating that this cytokine signature might be relevant for AIH pathogenesis. Our findings reemphasize the previously reported pathogenic role of IL-12 in murine AIH (19).…”

Functional heterogeneity of CD4+ T cells in liver inflammation

“…Furthermore, the presence of T H 17 cells and T cells coproducing IFN-γ and TNF-α was reported in AIH [12,103]: Findings indicated that TNF-α-producing CD4 + T cells were significantly expanded, both in blood and liver of AIH patients. However, the majority of the TNF-α-producing CD4 + T cells in AIH also co-produced IFN-γ, suggesting that these cells might represent a pathogenic activation state of T H 1 cells [12].…”

Role of CD4+ T-cells in the pathology of non-alcoholic fatty liver disease and related diseases

“…IFN-γ plays a crucial role in generating efficient innate and adaptive immune responses [134] . Studies have found an association of Th1 cells with organ-specific autoimmune diseases such as autoimmune type 1 diabetes [135] , rheumatoid arthritis [136] , multiple sclerosis [137] , and Crohn's disease [138] . In terms of liver diseases, Th1 cells are associated with AIH [139] , PBC [140] , and alcohol-related cirrhosis [141] .…”