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 nonfunctional intrahepatic CD8+T- cell responses. In light of dampened CD8(+) T-cell responses, liver disease often manifests systemically as immunoglobulin (Ig)-related syndromes due to aberrant B-cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4(+) T-cell help. Elevated CD4(+) forkhead box P3-positive (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 CD81 T-cell responses, aberrant B-cell activities were maintained due to expression of CD40 ligand on a subset of CD4(+) Foxp3(+) T cells. In vivo blockade of CD40 ligand attenuated B-cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4(+) Foxp31, CD40 ligand-positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. Conclusion: Liver disease elicits alterations in the intrahepatic CD4(+) T-cell compartment that suppress T-cell immunity while concomitantly promoting aberrant IgG mediated manifestations.