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 CD8 + 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 + Foxp3+, 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. (H epatology 2017;65:661‐677).