Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection
Anna B. Morris, … , Colleen S. Kraft, Mandy L. Ford
Anna B. Morris, … , Colleen S. Kraft, Mandy L. Ford
Published April 8, 2025
Citation Information: JCI Insight. 2025;10(7):e186259. https://doi.org/10.1172/jci.insight.186259.
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Research Article Immunology

Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection

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.

Authors

Anna B. Morris, Max W. Adelman, Kelsey B. Bennion, Catherine D. Martinez, Kem-Maria McCook, Michael H. Woodworth, Charles R. Langelier, Nadine Rouphael, Christopher D. Scharer, Cheryl L. Maier, Colleen S. Kraft, Mandy L. Ford

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Figure 4

Fgl2 is increased in the serum of patients with COVID and is associated with decreased circulating CD8+ T cells.

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Fgl2 is increased in the serum of patients with COVID and is associated ...
(A) Plasma obtained from n = 31 COVID+ patients (at 2–16, mean 8.9d following symptom onset) or n = 15 healthy patients was assayed for Fgl2 concentration (ng/mL) via ELISA. (B) PBMC was obtained from n = 31 patients testing positive for SARS CoV-2 admitted as inpatients at Emory University Hospital May-July 2020 (n = 31, Table 1) that were enrolled in an IRB-approved protocol and consented for blood draw. Blood samples were obtained 2-16 (mean 8.9) days after symptom onset. WBC were not available for n = 7 patients, thus all absolute count data represents n = 24 patients with COVID. Data were analyzed by Mann-Whitney U nonparametric test and are depicted as mean ± SEM. (B) Plasma concentration of Fgl2 (ng/mL) is plotted against the frequency of CD8+ cells among PBMC (left panel), the absolute number of CD8+ T cells within PBMC (right panel), or the frequency of CD8+ cells among PBMC in healthy controls (right panel). (C) Plasma concentration of Fgl2 (ng/mL) is plotted against the frequency of CD45RA+ CCR7– Tem among CD8+ cells (left panel), and the absolute number of CD8+ CD45RA+ CCR7– Tem within PBMC (right panel). (D) Plasma concentration of Fgl2 (ng/mL) is plotted against the absolute number of total FcγRIIB+CD8+ T cells within PBMC (left panel) and the number of FcγRIIB+CD8+CD45RA+CCR7– Tem within PBMC (right panel). (E) Frequency of FcγRIIB+ among CD8+ T cells is plotted against the frequency of CD8+ cells among PBMC (left panel), and the absolute number of CD8+ T cells within PBMC (right panel). Data were compared by linear regression analysis. (F and G) PBMC obtained from n = 21 patients positive for SARS-CoV-2 was subjected to bulk RNA-Seq (n = 10 patients did not have material available for RNA-Seq). (F) PCA of differentially expressed genes (DEG) between patients with high plasma Fgl2 concentrations versus those with low plasma Fgl2 concentrations. (G) GSEA of DEGs (FDR < 0.1). The normalized enrichment scores of significant pathways (FDR < 0.1) in patients exhibiting high versus low plasma Fgl2 concentrations are plotted.