Publication

GCNT1-Mediated -Glycosylation of the Sialomucin CD43 Is a Sensitive Indicator of Notch Signaling in Activated T Cells

Journal Paper/Review - Feb 14, 2020

Units
PubMed
Doi

Citation
Perkey E, Labrecque N, Nolz J, Brennan T, Siebel C, Blazar B, Ludewig B, Radtke F, Koch U, Granadier D, Dils A, Chung J, Carrington L, Maurice De Sousa D, Maillard I. GCNT1-Mediated -Glycosylation of the Sialomucin CD43 Is a Sensitive Indicator of Notch Signaling in Activated T Cells. J Immunol 2020; 204:1674-1688.
Type
Journal Paper/Review (English)
Journal
J Immunol 2020; 204
Publication Date
Feb 14, 2020
Issn Electronic
1550-6606
Pages
1674-1688
Brief description/objective

Notch signaling is emerging as a critical regulator of T cell activation and function. However, there is no reliable cell surface indicator of Notch signaling across activated T cell subsets. In this study, we show that Notch signals induce upregulated expression of the glycosyltransferase gene in T cells mediating graft-versus-host disease after allogeneic bone marrow transplantation in mice. To determine if mediated -glycosylation could be used as a Notch signaling reporter, we quantified the core-2 -glycoform of CD43 in multiple T cell subsets during graft-versus-host disease. Pharmacological blockade of Delta-like Notch ligands abrogated core-2 -glycosylation in a dose-dependent manner after allogeneic bone marrow transplantation, both in donor-derived CD4 and CD8 effector T cells and in Foxp3 regulatory T cells. CD43 core-2 -glycosylation depended on cell-intrinsic canonical Notch signals and identified CD4 and CD8 T cells with high cytokine-producing ability. -deficient T cells still drove lethal alloreactivity, showing that core-2 -glycosylation predicted, but did not cause, Notch-dependent T cell pathogenicity. Using core-2 -glycosylation as a marker of Notch signaling, we identified Ccl19-Cre fibroblastic stromal cells as critical sources of Delta-like ligands in graft-versus-host responses irrespective of conditioning intensity. Core-2 -glycosylation also reported Notch signaling in CD8 T cell responses to dendritic cell immunization, infection, and viral infection. Thus, we uncovered a role for Notch in controlling core-2 -glycosylation and identified a cell surface marker to quantify Notch signals in multiple immunological contexts. Our findings will help refine our understanding of the regulation, cellular source, and timing of Notch signals in T cell immunity.