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.
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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

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Figure 1

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Qa-1b expression on CD4 cell vaccine is essential for protection. Effect...
Qa-1b expression on CD4 cell vaccine is essential for protection. Effects of monoclonal anti–Qa-1 Ab on TCV in vitro (A) and in vivo (B). (A) C.AL-20 mice were vaccinated with CD4 cells isolated from HSV-1–infected C.AL-20 mice. A group of mice was vaccinated with the same CD4 cells but incubated with blocking anti–Qa-1 mAb (open squares) or isotype control (filled circles) or were nonvaccinated controls (open circles) as described in Methods. Two weeks later, vaccinated 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) C.AL-20 mice were intraperitoneally injected with anti–Qa-1 mAb (10 μg/mouse) at the time of TCV (open squares) or isotype control (filled circles) or were nonvaccinated controls (open circles). Two weeks later, vaccinated mice were ocularly infected with HSV-1 (KOS) and scored for HSK. Each group consisted of 10–20 mice, and results are representative of three independent experiments. (C) Qa-1 sorting. C.AL-20 mice were vaccinated with CD4 cells isolated from HSV-1–infected C.AL-20 mice. These CD4 cells were sorted according to their level of Qa-1 surface expression (high, filled triangles, versus low, filled squares) or nonvaccinated controls (open circles). Both groups were ocularly infected with HSV-1 (KOS) and scored for HSK as described in Methods. Each group consisted of 10–20 mice. Data are representative of two independent experiments.