GITR contributes to the systemic adjuvanticity of the Escherichia coli heat-labile enterotoxin.
The Escherichia coli heat-labile enterotoxin (LT) possesses a powerful mucosal and systemic adjuvant effect. However, little is known about the cellular and molecular basis of the immunostimulatory activity of LT at the mucosal level, and even less information is available on the mechanisms underlying its systemic adjuvant activity. In this study, we show that distinct mechanisms are responsible for the parenteral and mucosal adjuvanticity of LT. Indeed, the systemic administration of LT upregulates the expression of glucocorticoid-induced TNFR-related protein (GITR), but not other activation markers, in naive T cells. Using WT and GITR-deficient mice and LT and its enzymatically inactive mutant LTK63 as adjuvants, we show that the induction of GITR expression in T cells accounts for the systemic immunostimulatory capacity of LT, which requires an intact enzymatic activity. In contrast, the mucosal administration of LT does not induce GITR expression on Peyer's patche T cells and accordingly no differences are observed in the mucosal adjuvanticity of LT between WT and GITR-deficient mice. Altogether, our results demonstrate the distinct effect of LT after parenteral administration when compared with the mucosal delivery, and describe a new mechanism of LT adjuvanticity related to its ability to induce the expression of GITR in CD4(+) T cells.
Tamayo
Esther
E
Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
Postigo
Jorge
J
González
Jovanna
J
Fernández-Rey
Maigualida
M
Iglesias
Marcos
M
Santiuste
Inés
I
Riccardi
Carlo
C
Rappuoli
Rino
R
Del Giudice
Giuseppe
G
Merino
Ramón
R
Merino
Jesús
J
D000276:Adjuvants, Immunologic; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004768:Enterotoxins / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000276:immunology*; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018928:Immunity, Mucosal / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017475:Receptors, Nerve Growth Factor / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C027538:heat-labile enterotoxin, E coli