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

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.