Lymphocyte surface receptor that binds CAML and methods of use thereof

Abstract

A novel lymphocyte receptor protein, its DNA sequence, and its role in the calcium activation pathway is described. The protein, or genetically engineered constructs encoding it, are shown to increase lymphocyte response, and to identify ligands of the protein receptor. Antibodies to the proteins of the invention are generated for diagnostic therapeutics. The protein and DNA can also be used for diagnostic purposes and for identifying agents for modulating the calcium induced activation pathway. A particular advantage of the present invention is that it provides lymphocyte activation of receptor found on all B cells, but only on a subset of T cells. The receptor can thus be targeted to specifically regulate B cell responses without affecting mature T cell activity. Such targeting specificity is always advantageous, particularly where an increase or decrease of antibody production is desired, e.g., during an infection (increase) or to avoid immune complex deposition complications (rheumatoid arthritis, glomerulonephritis, and other auto immune conditions).

That which is claimed:  
     
         1 . A method of screening potential drugs to identify an immunosuppressant drug that blocks the action of B lymphocytes without blocking the activity of T lymphocytes, said method comprising: 
 (a) contacting a first lymphocyte with a potential drug; wherein the first lymphocyte contains a TACI protein and a first marker protein, and wherein said first marker protein is transcribed when TACI activity is stimulated in the absence of a candidate drug;    (b) stimulating TACI activity in the first lymphocyte;    (c) detecting the first marker protein; wherein a potential drug is identified as a candidate drug when the first marker protein is not detectable in the first lymphocyte;    (d) contacting a second lymphocyte with the candidate drug; wherein the second lymphocyte contains a T cell receptor and a second marker protein, and wherein said second marker protein is transcribed when the T cell receptor activity is stimulated either in the absence or the presence of an immunosuppressant drug;    (e) stimulating T cell receptor activity in the second lymphocyte;    (f) detecting the second marker protein, wherein a candidate drug is identified as an immunosuppressant drug when the second marker protein is detected in the second lymphocyte.    
     
     
         2 . The method of  claim 1 , wherein said TACI protein comprises an amino acid sequence having at least one conservative substitution in comparison with the amino acid sequence set forth in SEQ ID NO:1.  
     
     
         3 . The method of  claim 1 , wherein said TACI protein is encoded by a nucleotide sequence having at least 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         4 . The method of  claim 3 , wherein said TACI protein comprises the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         5 . The method of  claim 1 , wherein the step of stimulating TACI activity in the first lymphocyte is performed by contacting the first lymphocyte with an antibody that binds to the TACI protein.  
     
     
         6 . A method for screening candidate molecules to identify a ligand for a TACI protein, said method comprising: 
 (a) contacting a polypeptide comprising an N-terminal extracellular fragment of the TACI protein with a candidate molecule; and    (b) detecting the binding of the candidate to the polypeptide, where the binding of the candidate molecule to the polypeptide identifies the candidate molecule as a ligand.    
     
     
         7 . The method of  claim 6 , wherein the N-terminal extracellular fragment of the TACI protein comprises the amino acid sequence set forth in SEQ ID NO:6.  
     
     
         8 . The method of  claim 6 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         9 . The method of  claim 6 , wherein the N-terminal extracellular fragment of the TACI protein comprises an amino acid sequence having at least one conservative substitution in comparison with the amino acid sequence set forth in SEQ ID NO:6.  
     
     
         10 . The method of  claim 9 , wherein the polypeptide comprises an amino acid sequence having at least on conservative substitution in comparison with the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         11 . The method of  claim 6 , wherein binding of the candidate molecule to the polypeptide is detected by a method selected from the group consisting of: 
 (a) detecting activation of the AP-1 pathway;    (b) detecting activation of the CAML pathway;    (c) detecting activation of NF-AT;    (d) detecting activation of the NF-κB signaling pathway; and    (e) detecting activation of NF-AT mediated transcription.    
     
     
         12 . The method of  claim 6 , wherein the TACI protein is expressed in a yeast two-hybrid screen.  
     
     
         13 . The method of  claim 6 , wherein the polypeptide is expressed in Jurkat cells containing a reporter gene under the transcriptional control of an NF-AT promoter.  
     
     
         14 . A transgenic mouse whose genome is homozygous for an engineered disruption in the TACI gene, wherein said engineered disruption prevents the expression of a functional TACI protein.