Non‐neutralizing antibodies protect from chronic LCMV infection independently of activating FcγR or complement

Chronic viral infections lead to CD8⁺ T cell exhaustion, characterized by impaired cytokine secretion. The presence of the immune‐regulatory cytokine IL‐10 promotes chronic lymphocytic choriomeningitis virus (LCMV) Clone 13 infection in mice, whereas the absence of IL‐10/IL‐10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine‐producing T cells. However, it is currently unclear which cell populations and effector molecules are crucial to protect against chronic infection. In this study, we demonstrate that antiviral, LCMV‐binding, non‐neutralizing antibodies are needed, in addition to CD4⁺ and CD8⁺ T cells, to clear a high‐dose LCMV infection in mice, in the absence of IL‐10. The interaction between CD4⁺ T cells and B cells in B‐cell follicles via CD40/CD40L, in addition to class switch and/or somatic hypermutation, is crucial for viral control in the absence of IL‐10. Interestingly, transfer of LCMV‐binding non‐neutralizing antibodies protected recipients from chronic infection. In addition, viral clearance in the absence of IL‐10R signaling was independent of activating Fcγ receptors and complement. These data highlight that non‐neutralizing antibodies effectively contribute to the control of LCMV infection when present prior to infection, suggesting that the induction of neutralizing antibodies is not implicitly necessary for the generation of successful vaccines.