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 CD 8 + 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.

What is claimed is: 
     
         1 . A method of treating tumor in a subject, the method comprising the step of:
 administering to the subject an agent that specifically binds to a complex comprising a type B self peptide and HLA-E,   wherein the type B self peptide comprises the amino acid sequence set forth in SEQ ID NO: 15.   
     
     
         2 . The method of  claim 1 , wherein the agent specifically binds to (a) dendritic cells presenting a type B self peptide/HLA-E complex, (b) a membrane-bound, HLA-E-bearing composition binding to a type B self peptide, or (c) membrane-bound or lipid solublized HLA-E and a type B self peptide bound thereto. 
     
     
         3 . The method of  claim 1 , wherein the agent blocks or prevents the 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. 
     
     
         4 . The method of  claim 1 , wherein the agent is an antibody or an antigen-binding fragment thereof. 
     
     
         5 . The method of  claim 4 , wherein the agent is a monoclonal antibody. 
     
     
         6 . The method of  claim 5 , wherein the monoclonal antibody is a humanized monoclonal antibody. 
     
     
         7 . The method of  claim 1 , wherein the tumor is cancerous tumor or non-cancerous tumor. 
     
     
         8 . The method of  claim 7 , wherein the cancerous tumor is selected from the group consisting of biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms; liver cancer; lung cancer; lymphomas; neuroblastomas; oral cancer; ovarian cancer; pancreas cancer; prostate cancer; colorectal cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; and renal cancer. 
     
     
         9 . The method of  claim 8 , wherein the brain cancer is selected from the group consisting of glioblastomas and medulloblastomas. 
     
     
         10 . The method of  claim 8 , wherein the hematological neoplasm is selected from the group consisting of acute lymphocytic and myelogenous leukemia. 
     
     
         11 . The method of  claim 8 , wherein the intraepithelial neoplasm is selected from the group consisting of Bowen's disease and Paget's disease. 
     
     
         12 . The method of  claim 8 , wherein the lymphoma is selected from the group consisting of Hodgkin's disease and lymphocytic lymphomas. 
     
     
         13 . The method of  claim 8 , wherein the oral cancer is squamous cell carcinoma. 
     
     
         14 . The method of  claim 8 , wherein the ovarian cancer is selected from the group consisting of those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells. 
     
     
         15 . The method of  claim 8 , wherein the sarcoma is selected from the group consisting of leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma. 
     
     
         16 . The method of  claim 8 , wherein the skin cancer is selected from the group consisting of melanoma, Kaposi's sarcoma, basocellular cancer and squamous cell cancer. 
     
     
         17 . The method of  claim 8 , wherein the testicular cancer is selected from the group consisting of germinal tumors, stromal tumors and germ cell tumors. 
     
     
         18 . The method of  claim 17 , wherein the germinal tumor is selected from the group consisting of seminoma and non-seminoma. 
     
     
         19 . The method of  claim 18 , wherein the non-seminoma is selected from the group consisting of teratomas and choriocarcinomas. 
     
     
         20 . The method of  claim 8 , wherein the thyroid cancer is selected from the group consisting of thyroid adenocarcinoma and medullar carcinoma. 
     
     
         21 . The method of  claim 8 , wherein the renal cancer is selected from the group consisting of adenocarcinoma and Wilms tumor. 
     
     
         22 . The method of  claim 1 , wherein the type B self peptide is a Hsp60sp peptide consisting of SEQ ID NO: 2, or a structurally related peptide having from 70 to 99% similarity to SEQ ID NO: 2.