Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection

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Abstract
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.
Funding Information
  • National Institute of Allergy and Infectious Diseases (R01 AI164716)
  • National Institute of Allergy and Infectious Diseases (K23 AI144036)

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