Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes
Vily Panoutsakopoulou, … , Kai W. Wucherpfennig, Harvey Cantor
Vily Panoutsakopoulou, … , Kai W. Wucherpfennig, Harvey Cantor
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1218-1224. https://doi.org/10.1172/JCI20772.
View: Text | PDF
Article Immunology

Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes

Abstract

The ability of autoreactive T cells to provoke autoimmune disease is well documented. The finding that immunization with attenuated autoreactive T cells (T cell vaccination, or TCV) can induce T cell–dependent inhibition of autoimmune responses has opened the possibility that regulatory T cells may be harnessed to inhibit autoimmune disease. Progress in the clinical application of TCV, however, has been slow, in part because the underlying mechanism has remained clouded in uncertainty. We have investigated the molecular basis of TCV-induced disease resistance in two murine models of autoimmunity: herpes simplex virus-1 (KOS strain)–induced herpes stromal keratitis and murine autoimmune diabetes in non-obese diabetic (NOD) mice. We find that the therapeutic effects of TCV depend on activation of suppressive CD8 cells that specifically recognize Qa-1–bound peptides expressed by autoreactive CD4 cells. We clarify the molecular interaction between Qa-1 and self peptides that generates biologically active ligands capable of both inducing suppressive CD8 cells and targeting them to autoreactive CD4 cells. These studies suggest that vaccination with peptide-pulsed cells bearing the human equivalent of murine Qa-1 (HLA-E) may represent a convenient and effective clinical approach to cellular therapy of autoimmune disease.

Authors

Vily Panoutsakopoulou, Katharina M. Huster, Nami McCarty, Evan Feinberg, Rijian Wang, Kai W. Wucherpfennig, Harvey Cantor

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Vβ expression and TCV. (A) TCR Vβ8+ CD4 cells protect from development o...
Vβ expression and TCV. (A) TCR Vβ8+ CD4 cells protect from development of HSK. C.AL-20 mice were vaccinated with CD4 cells (as described in Methods) sorted according to TCR-Vβ expression (Vβ8+, filled circles; Vβ8−, open squares; Vβ2+, open circles). All mice were ocularly infected with HSV-1 (KOS) and scored for HSK. Each group consisted of ten mice, and results are representative of three independent experiments. (B) BALB/c mice were vaccinated with cells of either a TCR Vβ8+ CD4 T cell clone reactive to a corneal antigen (C1-6, open circles), or a CD4 T cell clone reactive to an OVA-derived peptide (DO11.10; open squares), or a TCR Vβ6+ CD4 T cell clone reactive to an OVA-derived peptide (O3; filled square), or were unvaccinated controls (filled circle). All mice were ocularly infected with HSV-1 (KOS) and scored for HSK. Each group consisted of ten mice, and results are representative of four independent experiments. (C) Binding of a TCR-derived Vβ8.1 peptide to Qa-1 renders O3 cells protective. C.AL-20 mice were vaccinated with pure cells of the TCR Vβ6+ CD4 T cell clone O3 (open squares) or O3 cells incubated with a TCR-derived Vβ8.1 peptide (open circles) or the mutated peptide L9D (filled circles). Two weeks later, all mice were ocularly infected with HSV-1 (KOS) and scored for HSK. Each group consisted of ten mice, and results are representative of three independent experiments.