Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection
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
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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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.