B7-h1, a novel immunoregulatory molecule

Abstract

The invention provides novel polypeptides useful for co-stimulating T cells, isolated nucleic acid molecules encoding them, vectors containing the nucleic acid molecules, and cells containing the vectors. Also included are methods of making and using these co-stimulatory polypeptides.

1 . An isolated DNA comprising:
 (a) a nucleic acid sequence that encodes a polypeptide with the ability to co-stimulate a T cell, wherein the nucleic acid sequence hybridizes under stringent conditions to the complement of a sequence that encodes a polypeptide with an amino acid sequence with SEQ ID NO:1 or SEQ ID NO:3; or   (b) the complement of the nucleic acid sequence.   
     
     
         2 . The DNA of  claim 1 , wherein the nucleic acid sequence encodes a polypeptide comprising an amino acid sequence with SEQ ID NO:1. 
     
     
         3 . The DNA of  claim 1 , wherein the nucleic acid sequence encodes a polypeptide comprising an amino acid sequence with SEQ ID NO:3. 
     
     
         4 . The DNA of  claim 1 , wherein the nucleic acid sequence has a sequence of SEQ ID NO:2. 
     
     
         5 . The DNA of  claim 1 , wherein the nucleic acid sequence has a sequence of SEQ ID NO:4. 
     
     
         6 . An isolated polypeptide encoded by the DNA of  claim 1 . 
     
     
         7 . The isolated polypeptide of  claim 6 , wherein the polypeptide comprises an amino acid sequence of amino acid residue 23 to amino acid residue 290 of SEQ ID NO:1, or said amino acid sequence but differing solely by conservative substitutions. 
     
     
         8 . The isolated polypeptide of  claim 6 , wherein the polypeptide comprises an amino acid sequence of amino acid residue 23 to amino acid residue 290 of SEQ ID NO:3, or said amino acid sequence but differing solely by conservative substitutions. 
     
     
         9 . The isolated polypeptide of  claim 6 , wherein the polypeptide comprises an amino acid sequence of SEQ ID NO:1, or said amino acid sequence but differing solely by conservative substitutions. 
     
     
         10 . The isolated polypeptide of  claim 6 , wherein the polypeptide comprises an amino acid sequence of SEQ ID NO:3, or said amino acid sequence but differing solely by conservative substitutions. 
     
     
         11 . A vector comprising the DNA of  claim 1 . 
     
     
         12 . The vector of  claim 11 , wherein the nucleic acid sequence is operably linked to a regulatory element which allows expression of said nucleic acid sequence in a cell. 
     
     
         13 . A cell comprising the vector of  claim 11 . 
     
     
         14 . A method of co-stimulating a T cell, the method comprising contacting the T cell with the polypeptide of  claim 6 . 
     
     
         15 . The method of  claim 14 , wherein the contacting comprises culturing the polypeptide with the T cell in vitro. 
     
     
         16 . The method of  claim 14 , wherein the T cell is in a mammal. 
     
     
         17 . The method of  claim 16 , wherein the contacting comprises administering the polypeptide to the mammal. 
     
     
         18 . The method of  claim 16 , wherein the contacting comprises administering a nucleic acid encoding the polypeptide to the mammal. 
     
     
         19 . The method of  claim 16 , comprising:
 (a) providing a recombinant cell which is the progeny of a cell obtained from the mammal and has been transfected or transformed ex vivo with a nucleic acid encoding the polypeptide so that the cell expresses the polypeptide; and   (b) administering the cell to the mammal.   
     
     
         20 . The method of  claim 19 , wherein the cell is an antigen presenting cell (APC) and the cell expresses the polypeptide on its surface. 
     
     
         21 . The method of  claim 20 , wherein, prior to the administering, the APC is pulsed with an antigen or an antigenic peptide. 
     
     
         22 . The method of  claim 16 , wherein the mammal is suspected of having an immunodeficiency disease. 
     
     
         23 . The method of  claim 16 , wherein the mammal is suspected of having an inflammatory condition. 
     
     
         24 . The method of  claim 16 , wherein the mammal is suspected of having an autoimmune disease. 
     
     
         25 . A method of identifying a compound that inhibits an immune response, the method comprising:
 (a) providing a test compound;   (b) culturing, together, the compound, the polypeptide of  claim 6 , a T cell, and a T cell activating stimulus; and   (c) determining whether the test compound inhibits the response of the T cell to the stimulus, as an indication that the test compound inhibits an immune response.   
     
     
         26 . The method of  claim 25 , wherein the stimulus is an antibody that binds to a T cell receptor or a CD3 polypeptide. 
     
     
         27 . The method of  claim 25 , wherein the stimulus is an alloantigen or an antigenic peptide bound to a major histocompatibility complex (MHC) molecule on the surface of an antigen presenting cell (APC). 
     
     
         28 . The method of  claim 27 , wherein the APC is transfected or transformed with a nucleic acid encoding the polypeptide and the polypeptide is expressed on the surface of the APC. 
     
     
         29 . A method of identifying a compound that enhances an immune response, the method comprising:
 (a) providing a test compound;   (b) culturing, together, the compound, the polypeptide of  claim 6 , a T cell, and a T cell activating stimulus; and   (c) determining whether the test compound enhances the response of the T cell to the antigen, as an indication that the test compound enhances an immune response.   
     
     
         30 . The method of  claim 29 , wherein the stimulus is an antibody that binds to a T cell receptor or a CD3 polypeptide. 
     
     
         31 . The method of  claim 29 , wherein the stimulus is an alloantigen or an antigenic peptide bound to a MHC molecule on the surface of an APC. 
     
     
         32 . The method of  claim 31 , wherein the APC is transfected or transformed with a nucleic acid encoding the polypeptide and the polypeptide is expressed on the surface of the APC. 
     
     
         33 . An antibody that binds specifically to the polypeptide of  claim 6 . 
     
     
         34 . The antibody of  claim 33 , wherein the antibody is a monoclonal antibody. 
     
     
         35 . The antibody of  claim 33 , wherein the antibody binds to the polypeptide with SEQ ID NO:1. 
     
     
         36 . A cell comprising the vector of  claim 12 . 
     
     
         37 . A method of producing a polypeptide that co-stimulates a T cell, the method comprising culturing the cell of  claim 36  and purifying the polypeptide from the culture. 
     
     
         38 . A fusion protein comprising a first domain joined to at least one additional domain, wherein the first domain comprises a polypeptide of  claim 6 . 
     
     
         39 . The fusion protein of  claim 38 , wherein the at least one additional domain comprises the constant region of an immunoglobulin heavy chain or a fragment thereof. 
     
     
         40 . A nucleic acid molecule encoding the fusion protein of  claim 39 . 
     
     
         41 . A vector comprising the nucleic acid molecule of  claim 40 . 
     
     
         42 . The vector of  claim 41 , wherein the nucleic acid molecule is operably linked to a regulatory element which allows expression of the nucleic acid molecule in a cell. 
     
     
         43 . A cell comprising the vector of  claim 42 . 
     
     
         44 . A method of producing a fusion protein, the method comprising culturing the cell of  claim 43  and purifying the fusion protein from the culture. 
     
     
         45 . The method of  claim 14 , wherein, the T cell is a helper T cell. 
     
     
         46 . The method of  claim 45 , wherein the helper T cell is a helper T cell that provides helper activity for a B cell antibody-producing response. 
     
     
         47 . The method of  claim 45 , wherein the B cell antibody response is an IgG2a antibody response. 
     
     
         48 . The method of  claim 14 , wherein the co-stimulation causes an increase in the level of CD40 ligand on the T cell surface.