Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes.
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.
Panoutsakopoulou
Vily
V
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Huster
Katharina M
KM
McCarty
Nami
N
Feinberg
Evan
E
Wang
Rijian
R
Wucherpfennig
Kai W
KW
Cantor
Harvey
H
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D016219:Immunotherapy, Adoptive; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination
D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C032907:Q surface antigens; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064655:V(D)J recombination activating protein 2