Fgl2 regulates FcγRIIB⁺CD8⁺ T cell responses during infection

While the inhibitory receptor FcγRIIB has been shown to be upregulated on activated CD8⁺ T cells in both mice and humans, its effect on T cell fate during infection has not been fully elucidated. We identified an increase in FcγRIIB-expressing CD8⁺ T cells in patients with COVID-19 relative to healthy controls as well as in mouse models of viral infection. Despite its well-known role as an Fc receptor, FcγRIIB also ligates the immunosuppressive cytokine Fgl2, resulting in CD8⁺ T cell apoptosis. Both chronic LCMV infection in mice and COVID-19 in humans resulted in a significant increase in plasma Fgl2. Transfer of CD8⁺ T cells into a Fgl2-replete, but not Fgl2-devoid, environment resulted in elimination of FcγRIIB⁺, but not FcγRIIB^–, CD8⁺ T cells. Similarly, plasma Fgl2 was directly proportional to CD8⁺ T cell lymphopenia in patients with COVID-19. RNA-Seq analysis demonstrated that Fgl2 was produced by murine virus–specific CD8⁺ T cells, with an increase in Fgl2 in CD8⁺ T cells elicited during chronic versus acute viral infection. Fgl2 was also upregulated in CD8⁺ T cells from patients with COVID-19 versus healthy controls. In summary, CD8⁺ T cell production of Fgl2 during viral infection underpinned an FcγRIIB-mediated loss of CD8⁺ T cell immunity in both mice and humans.