Peripheral CD27−CD21− B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis

•We examine the frequency and phenotype of CD27−CD21− B-cells in hepatitis C disease.•In non-cirrhotic and cirrhotic HCV, the CD27−CD21− B-cell population is expanded.•CD27−CD21− B-cells are hypoproliferative relative to other B-cell subsets.•Despite hypoproliferation, CD27−CD21− B-cells vigorously secrete IgG, IgM and IgA.

Hepatitis C cirrhosis is associated with a profound disappearance of memory B-cells. We sought to determine if this loss is associated with the expansion of the CD27−CD21− tissue-like memory B-cells with features of B-cell exhaustion. To this end, we quantified the frequency of CD27−CD21− B-cells in healthy, non-cirrhotic HCV-infected, and cirrhotic patients. We examined the expression of putative inhibitory receptors, the proliferative and immunoglobulin-secreting capacity of CD27/CD21-defined B-cell subsets upon B-cell receptor and/or CD40 stimulation. We found that CD27−CD21− B-cells are significantly increased in frequency relative to healthy donors in HCV-infected patients. CD27−CD21− B-cells were hypoproliferative relative to naïve and resting memory B-cells upon agonistic stimulation, but retained similar capacity for antibody secretion. Conclusion: CD27−CD21− tissue-like memory B-cells with exhausted proliferation circulate at increased frequency in cirrhotic and non-cirrhotic HCV-infected patients. This B-cell subset does not appear anergic, exhibiting immunoglobulin-secreting capacity on CD40 agonism indistinguishable from other CD27/CD21-defined B-cell subsets.