title: Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells.
abstract: CD28 is well characterized as a costimulatory molecule in T cell activation. Recent evidences indicate that TNFR superfamily members, including glucocorticoid-induced TNFR-related protein (GITR), act as costimulatory molecules. In this study, the relationship between GITR and CD28 has been investigated in murine CD8(+) T cells. When suboptimal doses of anti-CD3 Ab were used, the absence of GITR lowered CD28-induced activation in these cells whereas the lack of CD28 did not affect the response of CD8(+) T cells to GITR costimulus. In fact, costimulation of CD28 in anti-CD3-activated GITR(-/-) CD8(+) T cells resulted in an impaired increase of proliferation, impaired protection from apoptosis, and an impaired rise of activation molecules such as IL-2R, IL-2, and IFN-gamma. Most notably, CD28-costimulated GITR(-/-) CD8(+) T cells revealed lower NF-kappaB activation. As a consequence, up-regulation of Bcl-x(L), one of the major target proteins of CD28-dependent NF-kappaB activation, was defective in costimulated GITR(-/-) CD8(+) T cells. What contributed to the response to CD28 ligation in CD8(+) T cells was the early up-regulation of GITR ligand on the same cells, the effect of which was blocked by the addition of a recombinant GITR-Fc protein. Our results indicate that GITR influences CD8(+) T cell response to CD28 costimulation, lowering the threshold of CD8(+) T cell activation.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Tossicologia e Chemioterapia, Università di Perugia, and IBiT Foundation, Perugia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bianchini
authors.forename: L Tibor
authors.initials: LT
authors.lastname: Krausz
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D016328:NF-kappa B; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D051020:bcl-X Protein