Methods to activate or block the HLA-E/Qa-1 restricted CD8+ T cell regulatory pathway to treat immunological disease

Abstract

Methods are provided for inhibiting or enhancing down-regulation of an antigen-activated HLA-E+ T cell by an HLA-E-restricted CD8+ T cell comprising contacting the HLA-E* T cell and CD8+ T cell with an agent which inhibits or enhances, respectively, binding between (i) T cell receptor (TCR) on the surface of the CD8+ T cell and (ii) a self peptide presented by HLA-E on the surface of the HLA-E+ T cell, thereby inhibiting or enhancing, respectively, down-regulation of the antigen-activated HLA-E+ T cell. Compositions comprising agents which inhibit or enhance/activate, respectively, binding between (i) T cell receptor (TCR) on the surface of a CD8+ T cell and (ii) a self peptide presented by HLA-E on the surface of a HLA-E+ T cell, and assays for identifying such agents, are provided.

1 . A method for enhancing down-regulation of an antigen-activated HLA-E +  T cell by an HLA-E-restricted CD8 +  T cell comprising contacting the HLA-E +  T cell and CD8 +  T cell with an agent which enhances binding between (i) T cell receptor (TCR) on the surface of the CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of the HLA-E +  T cell, thereby enhancing down-regulation of the antigen-activated HLA-E +  T cell. 
     
     
         2 . The method of  claim 1 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         3 . The method of  claim 1 , wherein the HLA-E +  T cell is a CD8 + /HLA-E +  T cell. 
     
     
         4 . The method of  claim 1 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         5 . The method of  claim 1 , wherein the type B self peptide is a nonomer having the sequence set forth in SEQ ID NO:15. 
     
     
         6 . The method of  claim 4 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         7 . The method of  claim 1 , wherein the agent is a dendritic cell-derived, HLA-E-bearing exosome loaded with type B self peptide. 
     
     
         8 . The method of  claim 1 , wherein the agent is a dendritic cell-derived, HLA-E-bearing exosome loaded with Hsp60sp peptide. 
     
     
         9 . The method of  claim 1 , wherein the agent is an HLA-E/IgG fusion protein or an HLA-E/Hsp60sp tetramer. 
     
     
         10 . A method for enhancing down-regulation of an antigen-activated Qa-1 +  T cell by a Qa-1-dependent CD8 +  T cell comprising contacting the Qa-1 +  T cell and CD8 +  T cell with an agent which enhances binding between (i) T cell receptor (TCR) on the surface of the CD8 +  T cell and (ii) a type B self peptide presented by Qa-1 on the surface of the Qa-1 +  T cell, thereby enhancing down-regulation of the antigen-activated Qa-1 +  T cell. 
     
     
         11 . The method of  claim 10 , wherein the Qa-1 +  T cell is a CD4 + /Qa-1 +  T cell. 
     
     
         12 . The method of  claim 10 , wherein the Qa-1 +  T cell is a CD8 + /Qa-1 +  T cell. 
     
     
         13 . The method of  claim 10 , wherein the type B self peptide is Hsp60sp peptide. 
     
     
         14 . The method of  claim 10 , wherein the type B self peptide is a nonomer. 
     
     
         15 . The method of  claim 13 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         16 . The method of  claim 10 , wherein the agent is a dendritic cell-derived, Qa-1-bearing exosome loaded with type B self peptide. 
     
     
         17 . The method of  claim 10 , wherein the agent is a dendritic cell-derived, Qa-1-bearing exosome loaded with Hsp60sp peptide. 
     
     
         18 . The method of  claim 17 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         19 . The method of  claim 10 , wherein the agent is a Qa-1/IgG fusion protein. 
     
     
         20 . A method for enhancing down-regulation of antigen-activated HLA-E +  T cells by HLA-E-restricted CD8 +  T cells in a human subject comprising administering to the subject an effective amount of an agent which enhances binding between (i) a T cell receptor (TCR) on the surface of an HLA-E-restricted CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of an HLA-E +  T cell, thereby enhancing down-regulation of antigen-activated HLA-E +  T cells in the subject. 
     
     
         21 . The method of  claim 20 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         22 . The method of  claim 20 , wherein the HLA-E +  T cell is a CD8 + /HLA-E +  T cell. 
     
     
         23 . The method of  claim 20 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         24 . The method of  claim 20 , wherein the type B peptide is a nonomer having the sequence set forth in SEQ ID NO:15. 
     
     
         25 . The method of  claim 23 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         26 . The method of  claim 20 , wherein the agent is (i) a dendritic cell-derived, HLA-E-bearing exosome loaded with type B self peptide, or (ii) an HLA-E-bearing membrane-bounded composition loaded with type B self peptide. 
     
     
         27 . The method of  claim 20 , wherein the agent is (i) a dendritic cell-derived, HLA-E-bearing exosome loaded with Hsp60sp peptide, or (ii) an HLA-E-bearing membrane-bounded composition loaded with Hsp60sp peptide. 
     
     
         28 . The method of  claim 27 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         29 . The method of  claim 20 , wherein the agent is a HLA-E/IgG fusion protein or an HLA-E/Hsp60sp tetramer. 
     
     
         30 . The method of  claim 20 , wherein the agent is administered intravenously, intramuscularly or orally. 
     
     
         31 . A method for enhancing down-regulation of antigen-activated Qa-1 +  T cells by Qa-1-dependent CD8 +  T cells in a non-human subject comprising administering to the subject an effective amount of an agent which enhances binding between (i) a T cell receptor (TCR) on the surface of a Qa-1-dependent CD8 +  T cell and (ii) a type B self peptide presented by Qa-1 on the surface of a Qa-1 +  T cell, thereby enhancing down-regulation of the antigen activated Qa-1 +  T cells in the subject. 
     
     
         32 . The method of  claim 31 , wherein the Qa-1 +  T cell is a CD4 + /Qa-1 +  T cell. 
     
     
         33 . The method of  claim 31 , wherein the Qa-1 +  T cell is a CD8 + /Qa-1 +  T cell. 
     
     
         34 . The method of  claim 31 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         35 . The method of  claim 31 , wherein the type B self peptide is a nonomer. 
     
     
         36 . The method of  claim 31 , wherein the agent is (i) a dendritic cell-derived, Qa-1-bearing exosome loaded with type B self peptide, or (ii) a Qa-1-bearing membrane-bounded composition loaded with type B self peptide. 
     
     
         37 . The method of  claim 31 , wherein the agent is (i) a dendritic cell-derived, Qa-1-bearing exosome loaded with Hsp60sp peptide or, (ii) a Qa-1-bearing membrane-bounded composition loaded with Hsp60sp peptide. 
     
     
         38 . The method of  claim 34  or  37 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         39 . The method of  claim 31 , wherein the agent is administered intravenously, intramuscularly or orally. 
     
     
         40 . A method for treating a human subject afflicted with a disorder selected from the group consisting of an autoimmune disease, graft transplant rejection and bacterial infection comprising administering to the subject a therapeutically effective amount of an agent which enhances binding between (i) a T cell receptor (TCR) on the surface of an HLA-E-restricted CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of an HLA-E +  T cell, thereby treating the subject. 
     
     
         41 . The method of  claim 40 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         42 . The method of  claim 40 , wherein the HLA-E +  T cell is a CD8 + /HLA-E +  T cell. 
     
     
         43 . The method of  claim 40 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         44 . The method of  claim 40 , wherein the type B self-peptide is a nonomer. 
     
     
         45 . The method of  claim 40 , wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis and type 1 diabetes. 
     
     
         46 . The method of  claim 40 , wherein the agent is (i) a dendritic cell-derived, HLA-E-bearing exosome loaded with type B self peptide, or (ii) an HLA-E-bearing membrane-bounded composition loaded with type B self peptide. 
     
     
         47 . The method of  claim 40 , wherein the agent is (i) a dendritic cell-derived, HLA-E-bearing exosome loaded with Hsp60sp peptide, or (ii) an HLA-E-bearing membrane-bounded composition loaded with Hsp60sp peptide. 
     
     
         48 . The method of  claim 43  or  47 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         49 . The method of  claim 40 , wherein the agent is an HLA-E/IgG fusion protein. 
     
     
         50 . The method of  claim 40 , wherein the agent is a HLA-E/Hsp60sp tetramer. 
     
     
         51 . The method of  claim 40 , wherein the agent is administered intravenously, intramuscularly or orally. 
     
     
         52 . A method for inhibiting in a human subject the onset of a disorder selected from the group consisting of an autoimmune disease, graft transplant rejection and bacterial infection comprising administering to the subject a prophylactically effective amount of an agent which enhances binding between (i) a T cell receptor (TCR) on the surface of an HLA-E-restricted CD8 +  T cell and (ii) a type-B self peptide presented by HLA-E on the surface of an HLA-E +  T cell, thereby treating the subject. 
     
     
         53 . The method of  claim 52 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         54 . The method of  claim 52 , wherein the HLA-E +  T cell is a CD8 + /HLA-E +  T cell. 
     
     
         55 . The method of  claim 52 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         56 . The method of  claim 52 , wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, type 1 diabetes, alopecia greata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, crest syndrome, Crohn's disease, Dego's disease, dermatomyositis, juvenile dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Grave's disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IGA nephropathy, juvenile arthritis, lupus, Meniere's disease, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis. 
     
     
         57 . The method of  claim 52 , wherein the agent is (i) a dendritic cell-derived, HLA-E-bearing exosome loaded with type B self peptide, or (ii) an HLA-E-bearing membrane-bounded composition loaded with type B self peptide. 
     
     
         58 . The method of  claim 52 , wherein the agent is (i) a dendritic cell-derived, HLA-E-bearing exosome loaded with Hsp60sp peptide, or (ii) an HLA-E-bearing membrane-bounded composition loaded with Hsp60sp peptide. 
     
     
         59 . The method of  claim 52 , wherein the agent is a HLA-E/IgG fusion protein. 
     
     
         60 . The method of  claim 52 , wherein the agent is a HLA-E/Hsp60sp tetramer. 
     
     
         61 . The method of  claim 52 , wherein the agent is administered intravenously, intramuscularly or orally. 
     
     
         62 . A dendritic cell-derived, Qa-1-bearing exosome loaded with self peptide. 
     
     
         63 . The exosome of  claim 62 , wherein the exosome is loaded with a type B self peptide. 
     
     
         64 . The exosome of  claim 62 , wherein the exosome is loaded with Hsp60sp peptide or a structurally related peptide. 
     
     
         65 . A dendritic cell-derived, HLA-E-bearing exosome loaded with self peptide. 
     
     
         66 . The exosome of  claim 65 , wherein the exosome is loaded with a type B self peptide. 
     
     
         67 . The exosome of  claim 65 , wherein the exosome is loaded with Hsp60sp peptide or a structurally related peptide. 
     
     
         68 . The exosome of  claim 64  or  67 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         69 . A membrane-bounded composition bearing Qa-1 and comprising type B self peptide. 
     
     
         70 . The composition of  claim 69 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         71 . A membrane-bounded composition bearing HLA-E and comprising type B self peptide. 
     
     
         72 . The composition of  claim 71 , wherein the type B self peptide is Hsp60sp peptide. 
     
     
         73 . A method for inhibiting down-regulation of an antigen-activated HLA-E +  T cell by an HLA-E-restricted CD8 +  T cell comprising contacting the HLA-E +  T cell and CD8 +  T cell with an agent which inhibits binding between (i) T cell receptor (TCR) on the surface of the CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of the HLA-E +  T cell, thereby inhibiting down-regulation of the antigen-activated HLA-E +  T cell. 
     
     
         74 . The method of  claim 73 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         75 . The method of  claim 73 , wherein the HLA-E +  T cell is a CD8 + /HLA-E +  T cell. 
     
     
         76 . The method of  claim 73 , wherein the type B self peptide is the leader sequence of Heat Shock Protein 60 (Hsp60sp peptide). 
     
     
         77 . The method of  claim 76 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth set forth in SEQ ID NO:2 
     
     
         78 . The method of  claim 73 , wherein the agent is an antibody which specifically binds to a complex comprising the type B self peptide and the HLA-E. 
     
     
         79 . The method of  claim 73 , wherein the agent is an antibody which specifically binds to a complex comprising an Hsp60sp peptide and the HLA-E. 
     
     
         80 . A method for inhibiting down-regulation of an antigen-activated Qa-1 +  T cell by a Qa-1-dependent CD8 +  T cell comprising contacting the Qa-1 +  T cell and CD8 +  T cell with an agent which inhibits binding between (i) T cell receptor (TCR) on the surface of the CD8 +  T cell and (ii) a type B self peptide presented by Qa-1 on the surface of the Qa-1 +  T cell, thereby inhibiting down-regulation of the antigen-activated Qa-1 +  T cell. 
     
     
         81 . The method of  claim 80 , wherein the Qa-1 +  T cell is a CD4 +/Qa- 1 +  T cell. 
     
     
         82 . The method of  claim 80 , wherein the Qa-1 +  T cell is a CD8 + /Qa-1 +  T cell. 
     
     
         83 . The method of  claim 80 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         84 . The method of  claim 80 , wherein the agent is an antibody which specifically binds to a complex comprising the type B self peptide and the Qa-1. 
     
     
         85 . The method of  claim 80 , wherein the agent is an antibody which specifically binds to a complex comprising the Hsp60sp peptide and the Qa-1. 
     
     
         86 . A method for inhibiting down-regulation of antigen-activated HLA-E +  T cells by HLA-E-restricted CD8 +  T cells in a human subject comprising administering to the subject an effective amount of an agent which inhibits binding between (i) a T cell receptor (TCR) on the surface of an HLA-E-restricted CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of an HLA-E +  T cell, thereby inhibiting down-regulation of antigen-activated HLA-E +  T cells in the subject. 
     
     
         87 . The method of  claim 86 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         88 . The method of  claim 86 , wherein the HLA-E +  T cell is a CD8 + /HLA-E +  T cell. 
     
     
         89 . The method of  claim 86 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         90 . The method of  claim 89 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         91 . The method of  claim 86 , wherein the agent is an antibody which specifically binds to a complex comprising a type B self peptide and the HLA-E. 
     
     
         92 . The method of  claim 86 , wherein the agent is an antibody which specifically binds to a complex comprising Hsp60sp peptide and the HLA-E. 
     
     
         93 . The method of  claim 86 , wherein the agent is administered intravenously, intramuscularly or orally. 
     
     
         94 . A method for treating a human subject afflicted with a disorder characterized by excessive CD8 +  T cell-mediated immunosuppression comprising administering to the subject a therapeutically effective amount of an agent which inhibits binding between (i) a T cell receptor (TCR) on the surface of an HLA-E-restricted CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of an HLA-E +  T cell, thereby treating the subject. 
     
     
         95 . The method of  claim 94 , wherein the HLA-E +  T cell is a CD4 + /HLA-E +  T cell. 
     
     
         96 . The method of  claim 94 , wherein the HLA-E +  T cell is a CD8/HLA-E +  T cell. 
     
     
         97 . The method of  claim 94 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         98 . The method of  claim 94 , wherein the agent is an antibody which specifically binds to a complex comprising type B self peptide and the HLA-E. 
     
     
         99 . The method of  claim 94 , wherein the agent is an antibody which specifically binds to a complex comprising Hsp60sp peptide and the HLA-E. 
     
     
         100 . The method of  claim 94 , wherein the subject is afflicted with AIDS. 
     
     
         101 . The method of  claim 94 , wherein the subject is afflicted with a tumor. 
     
     
         102 . The method of  claim 101 , wherein the subject has previously undergone treatment with a tumor vaccine or autologous T cell therapy. 
     
     
         103 . The method of  claim 94 , wherein the agent is administered intravenously, intramuscularly or orally. 
     
     
         104 . An isolated antibody which specifically binds to a complex comprising a type B self peptide and Qa-1. 
     
     
         105 . The antibody of  claim 104 , wherein the type B self peptide is Hsp60sp peptide. 
     
     
         106 . The antibody of  claim 105 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         107 . The antibody of  claim 104 , wherein the antibody is a monoclonal antibody. 
     
     
         108 . An isolated antibody which specifically binds to a complex comprising a type B self peptide and HLA-E. 
     
     
         109 . The antibody of  claim 108 , wherein the type B peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         110 . The antibody of  claim 109 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         111 . The antibody of  claim 108 , wherein the antibody is a monoclonal antibody. 
     
     
         112 . A composition consisting essentially of membrane-bound or lipid solublized HLA-E and a type B self peptide bound thereto. 
     
     
         113 . The composition of  claim 137 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         114 . The composition of  claim 113 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         115 . A composition consisting essentially of (i) a membrane-bound or lipid solublized HLA-E and a type B self peptide bound thereto, and (ii) a pharmaceutically acceptable carrier. 
     
     
         116 . A composition consisting essentially of membrane-bound or lipid solublized Qa-1 and a type B self peptide bound thereto. 
     
     
         117 . The composition of  claim 116 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         118 . The composition of  claim 117 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         119 . A composition consisting essentially of (i) a membrane-bound or lipid solubilized Qa-1 and a self peptide bound thereto, and (ii) a pharmaceutically acceptable carrier. 
     
     
         120 . A composition comprising a pharmaceutically acceptable carrier and an antibody which specifically binds to a type B self peptide presented by Qa-1. 
     
     
         121 . The composition of  claim 120 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         122 . A composition comprising a pharmaceutically acceptable carrier and an antibody which specifically binds to a type B self peptide presented by HLA-E. 
     
     
         123 . The composition of  claim 122 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         124 . The composition of  claim 123 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         125 . A composition comprising the exosome of  claim 64  or of  claim 67  and a pharmaceutically acceptable carrier. 
     
     
         126 . A composition comprising the membrane-bounded composition of  claims 69  and  71  and a pharmaceutically acceptable carrier. 
     
     
         127 . A method for determining if a CD8 +  T cell is a Qa-1-dependent CD8 +  T cell, comprising contacting the CD8 +  T cell with a type-B self peptide presented by Qa-1, and determining whether binding occurs between the CD8 +  T cell and the type B self peptide, whereby binding indicates that the CD8 +  T cell is a Qa-1-dependent CD8 +  T cell. 
     
     
         128 . The method of  claim 127 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         129 . The method of  claim 128 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         130 . The method of  claim 127 , wherein the type B self peptide is presented by Qa-1 present on (i) a dendritic cell-derived, Qa-1-bearing exosome or (ii) a Qa-1-bearing membrane-bounded composition. 
     
     
         131 . A method for determining if a CD8 +  T cell is an HLA-E-restricted CD8 +  T cell, comprising contacting the CD8 +  T cell with a type B self peptide presented by HLA-E, and determining whether binding occurs between the CD8 +  T cell and the type B self peptide, whereby binding indicates that the CD8 +  T cell is an HLA-E-restricted CD8 +  T cell. 
     
     
         132 . The method of  claim 131 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         133 . The method of  claim 132 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         134 . The method of  claim 131 , wherein the type B self peptide is presented by HLA-E present on (i) a dendritic cell-derived, HLA-E-bearing exosome or (ii) an HLA-E-bearing membrane-bounded composition. 
     
     
         135 . A method for isolating Qa-1-dependent CD8 +  T cells present in a T cell-containing sample comprising:
 (a) contacting the sample with an immobilized Qa-1-presented type B self peptide under conditions permitting binding of the type B self peptide with Qa-1-dependent CD8 +  T cells in the sample;   (b) removing unbound T cells; and   (c) dissociating from the immobilized type B self peptide any bound Qa-1-dependent CD8 +  T cells,   
       thereby isolating Qa-1-dependent CD8 +  T cells from the sample. 
     
     
         136 . The method of  claim 135 , wherein the type B self peptide comprises the signal peptide of Heat Shock Protein60 as set forth in SEQ ID NO:2. 
     
     
         137 . A method for isolating HLA-E-restricted CD8 +  T cells present in a T cell-containing sample comprising:
 (a) contacting the sample with immobilized HLA-E-presented type B self peptide under conditions permitting binding of the type B self peptide with HLA-E-restricted CD8 +  T cells in the sample;   (b) removing unbound T cells; and   (c) dissociating from the immobilized type B self peptide any bound HLA-E-restricted CD8 +  T cells,   
       thereby isolating HLA-E-restricted CD8 +  T cells from the sample. 
     
     
         138 . The method of  claim 137 , wherein the type B self peptide comprises the leader sequence of Heat Shock Protein60 as set forth in SEQ ID NO:2. 
     
     
         139 . A method of identifying an agent as an enhancer of down-regulation of antigen-activated intermediate avidity Qa-1 +  T cells by Qa-1-dependent CD8 +  T cells comprising:
 a) providing an antigen-activated Qa-1 +  T cell and a Qa-1-dependent CD8 +  T cell;   b) contacting the antigen-activated Qa-1 +  T cell with the Qa-1-dependent CD8 +  T cell;   c) quantitating down-regulation of the antigen-activated Qa-1 +  T cell;   d) repeating steps b) and c) in the presence of the agent;   e) comparing the down-regulation quantitated in step d) with the down-regulation quantitated in step c),   
       wherein down-regulation quantitated in step d) greater than that quantitated in step c) indicates that the agent is an enhancer of down-regulation of antigen-activated intermediate avidity Qa-1 +  T cells by Qa-1-dependent CD8 +  T cells. 
     
     
         140 . A method of identifying an agent as an enhancer of down-regulation of antigen-activated intermediate avidity HLA-E +  T cells by HLA-E-restricted CD8 +  T cells comprising:
 a) providing an antigen-activated HLA-E +  T cell and a HLA-E-restricted CD8 +  T cell;   b) contacting the activated HLA-E +  T cell with the HLA-E-restricted CD8 +  T cell;   c) quantitating down-regulation of the activated HLA-E +  T cell;   d) repeating steps b) and c) in the presence of the agent;   e) comparing the down-regulation quantitated in step d) with the down-regulation quantitated in step c),   
       wherein down-regulation quantitated in step d) greater than that quantitated in step c) indicates that the agent is an enhancer of down-regulation of antigen activated intermediate avidity HLA-E +  T cells by HLA-E-restricted CD8 +  T cells. 
     
     
         141 . A method of identifying an agent as an inhibitor of down-regulation of intermediate avidity antigen-activated Qa-1 +  T cells by Qa-1-dependent CD8 +  T cells comprising:
 a) providing an activated Qa-1 +  T cell and a Qa-1-dependent CD8 +  T cell;   b) contacting the activated Qa-1 +  T cell with the Qa-1-dependent CD8 +  T cell;   c) quantitating down-regulation of the activated Qa-1 +  T cell;   d) repeating steps b) and c) in the presence of the agent;   e) comparing the down-regulation quantitated in step d) with the down-regulation quantitated in step c),   
       wherein down-regulation quantitated in step d) less than that quantitated in step c) indicates that the agent is an inhibitor of down-regulation of intermediate avidity antigen-activated Qa-1 +  T cells by Qa-1-dependent CD8 +  T cells. 
     
     
         142 . A method of identifying an agent as an inhibitor of down-regulation of intermediate avidity antigen-activated HLA-E +  T cells by HLA-E-restricted CD8 +  T cells comprising:
 a) providing an activated HLA-E +  T cell and a HLA-E-restricted CD8 +  T cell;   b) contacting the activated HLA-E +  T cell with the HLA-E-restricted CD8 +  T cell;   c) quantitating down-regulation of the activated HLA-E +  T cell;   d) repeating steps b) and c) in the presence of the agent;   e) comparing the down-regulation quantitated in step d) with the down-regulation quantitated in step c),   
       wherein down-regulation quantitated in step d) less than that quantitated in step c) indicates that the agent is an inhibitor of down-regulation of intermediate avidity antigen-activated HLA-E +  cells by HLA-E-restricted CD8 +  T cells. 
     
     
         143 . The method of  claim 139  or  141 , wherein the Qa-1 +  T cells are human Qa-1 +  T cells. 
     
     
         144 . The method of  claim 140  or  142 , wherein the HLA-E +  T cells are human HLA-E +  T cells. 
     
     
         145 . The method of  claim 140  or  142 , wherein the agent is a nonomer peptide. 
     
     
         146 . The method of  claim 145 , wherein the nonomer peptide has a methionine or a leucine at P2 and a leucine at P9. 
     
     
         147 . A method of inhibiting down-regulation of an antigen-activated HLA-E +  T cell by an HLA-E-restricted CD8 +  T cell comprising introducing a nucleic acid into the HLA-E +  T cell or CD8 +  T cell so as to inhibit binding between (i) T cell receptor (TCR) on the surface of the CD8 +  T cell and (ii) a type B self peptide presented by HLA-E on the surface of the HLA-E +  T cell, thereby inhibiting down-regulation of the antigen-activated HLA-E +  T cell. 
     
     
         148 . The method of  claim 145 , wherein the nucleic acid is siRNA. 
     
     
         149 . A method of selectively activating a HLA-E-restricted regulatory CD8 +  T cell comprising contacting the HLA-E-restricted regulatory CD8 +  T cell with an HLA-E/Hsp60sp tetramer or an HLA-e/IgG fusion protein so as to thereby selectively activate the HLA-E-restricted regulatory CD8 +  T cell. 
     
     
         150 . The method of  claim 149 , wherein the HLA-E-restricted CD8 +  T cell is contacted with an HLA-E/Hsp60sp tetramer. 
     
     
         151 . The method of  claim 149 , wherein the HLA-E-restricted CD8 +  T cell is contacted with an HLA-e/IgG fusion protein. 
     
     
         152 . A method of inhibiting an antigen-activated HLA-E +  T cell comprising contacting an HLA-E-restricted CD8 +  T cell with an HLA-E/Hsp60sp tetramer or an HLA-e/IgG fusion protein so as to activate the HLA-E-restricted CD8 +  T cell and thereby inhibit the HLA-E +  T cell. 
     
     
         153 . The method of  claim 152 , wherein the HLA-E-restricted CD8 +  T cell is contacted with an HLA-E/Hsp60sp tetramer. 
     
     
         154 . The method of  claim 152 , wherein the HLA-E-restricted CD8 +  T cell is contacted with an HLA-E/IgG fusion protein. 
     
     
         155 . A method of treating an autoimmune disease in a subject comprising administering to the subject an amount of an agent effective to activate an HLA-E-restricted CD8 +  T cell so as to thereby inhibit an activated HLA-E +  T cell in the subject and thereby treat the autoimmune disease. 
     
     
         156 . The method of  claim 155 , wherein the agent is an HLA-E/Hsp60sp tetramer or an HLA-E/IgG fusion protein. 
     
     
         157 . A method of determining the efficacy of an autoimmune disease treatment comprising:
 a) quantifying the activated HLA-E +  T cells in a first sample obtained from the subject before treatment;   b) treating the subject with the autoimmune disease treatment;   c) quantifying the activated HLA-E +  T cells in a second sample obtained from the subject after treatment;   d) comparing the level of activated HLA-E +  T cells quantified in steps a) and c) wherein a lower level quantified in step c) than step a) indicates that the autoimmune disease treatment is efficacious.   
     
     
         158 . The method of  claim 157 , wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, type 1 diabetes, alopecia greata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, crest syndrome, Crohn's disease, Dego's disease, dermatomyositis, juvenile dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Grave's disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IGA nephropathy, juvenile arthritis, lupus, Meniere's disease, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis. 
     
     
         159 . The method of  claim 157 , wherein the activated HLA-T cells are quantified by contacting the sample with an HLA-E/Hsp60sp tetramer or an HLA-E/IgG fusion protein and quantifying the binding of the HLA-E +  T cells to the HLA-E/Hsp60sp tetramer or to the HLA-E/IgG fusion protein. 
     
     
         160 . The method of  claim 159  wherein the HLA-E/Hsp60sp tetramer or the HLA-E/IgG is immobilized. 
     
     
         161 . The method of  claim 157  wherein the samples are derived from the subject's blood or derived from the subject's lymph. 
     
     
         162 . A process of manufacturing a pharmaceutical for treating an autoimmune disease comprising:
 g) identifying an agent that enhances binding between an HLA-E-restricted CD8 +  T cell and an antigen-activated HLA-E +  T cell; and   h) admixing the agent identified in step a) with a pharmaceutically acceptable carrier so as to thereby manufacture the pharmaceutical.   
     
     
         163 . The process of  claim 162  wherein in step a) the agent is identified as enhancing binding by i) providing an antigen-activated HLA-E+ T cell and a HLA-E-restricted CD8+ T cell; ii) contacting the activated HLA-E+ T cell with the HLA-E-restricted CD8+ T cell; iii) quantitating down-regulation of the activated HLA-E+ T cell; iv) repeating steps ii) and iii) in the presence of the agent; v) comparing the down-regulation quantitated in step iv) with the down-regulation quantitated in step iii), wherein down-regulation quantitated in step iv) greater than that quantitated in step iii) identifies the agent an enhancer of down-regulation of antigen-activated HLA-E+ T cells by HLA-E-restricted CD8+ T cells. 
     
     
         164 . A vaccine composition comprising a membrane-bound HLA-E or lipid-solublized HLA-E and a type B self peptide bound thereto. 
     
     
         165 . The vaccine composition of  claim 164 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         166 . The vaccine composition of  claim 165 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         167 . The vaccine composition of  claim 164 , wherein the type B self peptide has the sequence set forth in SEQ ID NO:15. 
     
     
         168 . A vaccine composition consisting essentially of (i) a membrane-bound HLA-E or lipid-solublized HLA-E and a type B self peptide bound thereto, and (ii) a pharmaceutically acceptable carrier. 
     
     
         169 . The vaccine composition of  claim 168 , wherein the type B self peptide is Hsp60sp peptide or a structurally related peptide. 
     
     
         170 . The vaccine composition of  claim 169 , wherein the Hsp60sp peptide comprises consecutive amino acids having the sequence set forth in SEQ ID NO:2. 
     
     
         171 . The vaccine composition of  claim 168 , wherein the type B self peptide has the sequence set forth in SEQ ID NO:15. 
     
     
         172 . A vaccine composition comprising HLA-E and a type B self peptide bound thereto. 
     
     
         173 . A vaccine composition comprising an HLA-E/type B self peptide tetramer. 
     
     
         174 . The vaccine composition of  claim 172  or  173 , comprising a pharmaceutically acceptable carrier. 
     
     
         175 . The vaccine composition of  claim 172  or  173 , wherein the type B self peptide is Hsp60sp. 
     
     
         176 . An isolated peptide having the sequence set forth in SEQ ID NO:2.