CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T‐cell suppression during chronic liver disease

Abstract

Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to non-functional intrahepatic CD8+ T cell responses. In light of dampened CD8+ T cell responses, liver disease often manifests systemically as Ig-related syndromes due to aberrant B cell functions. These two opposing yet co-existing phenomena implicate the potential of altered CD4+ T cell help. Elevated CD4+ Foxp3+ T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8+ T cell responses, aberrant B cell activities were maintained due to expression of CD40L on a subset of CD4+ Foxp3+ T cells. In vivo blockade of CD40L attenuated B cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4+ Foxp3+ CD40L+ T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in non-diseased liver tissues and peripheral blood.Conclusion-Our data indicate that liver disease elicits alterations in the intrahepatic CD4+ T cell compartment that suppress T cell immunity while concomitantly promoting aberrant IgGmediated manifestations. (9) and in human patients (5,6,10). While this is beneficial for the liver, this population has been implicated in aiding establishment of chronic hepatotropic infections, such as HCV, in human patients by suppressing CD8+ T cell responses (6,11,12). Aside from the effects on CD4+ T cell functions, HSC-derived RA can augment B cell survival, plasmablast differentiation and IgG production (4). Aberrant B cell function during liver fibrosis has been linked to systemic manifestations such as hyperglobulinemia, elevated titers of autoimmune anti-nuclear antibody (ANA), and mixed cryoglobulinemia (MC) (reviewed in (13)). The dual effects of fibrotic processes on local suppression of CD8+ T cell responses by accumulation of CD4+Foxp3+T cells with concomitant dysfunctional intrahepatic B cells suggests a potential interplay between fibrosis, CD4+ T cell helper functions and B cells. KeywordsHere, we investigated the effects of hepatic fibrosis on the CD4+ T cell compartment and its consequence on the IgG-mediated sequelae of liver disease. Using chemically induced liver injury in mice we found that fibrotic animals demonstrated a CD4+ T cell-dependent increase in serum IgG levels. Despite constitutive intrahepatic B cell production of IgG, there was a liver-specific accumulation of "regulatory" CD4+Foxp3+ T cells during liver injury. Fibrosis-elicited CD4+Foxp3+ T cells effectively suppressed CD8+ T cell responses to cognate antigen while concomitantly permitting B cell activation in vitro. Phenotypic analysis demonstrated that a subset of the fibrosis-elicited CD4+Foxp3+ T cell population expressed CD40L and failed to suppress B cell functions in vitro. In accordance to our findings in the mouse model,...

Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

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Foxp3+ Regulatory T Cells Inhibit CCl4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity

“…Foxp3+ regulatory T (Treg) cells play a pivotal role in maintaining immunological self-tolerance and tissue homeostasis by regulating inappropriate immune responses to self-organs and tissues ( 3 ). Under various pathogenic conditions in humans and animal models, Treg cells are recruited into the liver to regulate tissue inflammation and pathology ( 4 – 8 ). There is also accumulated evidence that tissue Treg cells actively engage in tissue remodeling and repair in stressed or damaged organs, for example, by secreting amphiregulin, a key molecule for tissue regeneration and repair in various inflammation models, including brain ischemia, muscle injury, and viral pneumonia ( 9 – 11 ).…”

Environmental peer pressure: CD4+ T cell help in tolerance and transplantation

“…Thus, any renal recovery following hepatic transplantation alone may simply be the outcome of successful engraftment and regained liver function . In addition to physiologic perturbations, the intrahepatic milieu fundamentally changes in such a way that implicates aberrant immune responses such as constitutive antibody production . Accordingly, ESLD‐related increases in serum antibody content and immune complexes can potentially accumulate and cause kidney damage .…”

“…1). (38) In addition, during liver injury, activated hepatocytes produce complement proteins, which are key mediators of liver repair. (39)(40)(41) Consequently, studies in human peripheral blood mononuclear cells have found that stimulation through CD46, the complement receptor, in the presence of professional APCs (ie, monocytes and DCs) and inflammatory cytokines can also induce Foxp3 expression on CD4 1 T cells.…”

“…(56) In addition to physiologic perturbations, the intrahepatic milieu fundamentally changes in such a way that implicates aberrant immune responses such as constitutive antibody production. (38,57) Accordingly, ESLD-related increases in serum antibody content and immune complexes can potentially accumulate and cause kidney damage. (27,44) In either case, liver transplantation could conceivably reconstitute kidney function in ESLD patients as well as alleviate aberrant immune responses.…”