Methods and compositions for generating an immune response by inducing cd40 and pattern recognition receptors and adaptors thereof

Abstract

Provided are methods for activating an antigen-presenting cell and eliciting an immune response by inducing pattern recognition receptor activity, and CD40 activity. Also provided are methods for activating an antigen-presenting cell and eliciting an immune response by inducing CD40 activity without prostaglandin E2. Also provided are methods for activating an antigen-presenting cell and eliciting an immune response by inducing an inducible chimeric molecule comprising a region of a pattern recognition receptor or an adaptor thereof.

What is claimed is: 
     
         1 . A composition which comprises a nucleic acid having a polynucleotide sequence that encodes a chimeric protein, wherein the chimeric protein comprises (i) a membrane targeting region, (ii) a ligand-binding region that binds to a multimeric non-protein ligand, and (iii-a) a signaling region and/or cytoplasmic region of a pattern recognition receptor (PRR) or (iii-b) an adapter of a PRR. 
     
     
         2 . The composition of  claim 1 , wherein the chimeric protein comprises a CD40 cytoplasmic polypeptide region lacking the CD40 extracellular domain. 
     
     
         3 . The method of  claim 1 , wherein the chimeric protein comprises a signaling region and/or cytoplasmic region of a PRR. 
     
     
         4 . The composition of  claim 1 , wherein the PRR is a NOD-like PRR. 
     
     
         5 . The composition of  claim 4 , wherein the NOD-like PRR is a NOD1 PRR. 
     
     
         6 . The composition of  claim 4 , wherein the NOD-like PRR is a NOD2 PRR. 
     
     
         7 . The composition of  claim 1 , wherein the PRR is a RIG-like helicase. 
     
     
         8 . The composition of  claim 7 , wherein the RIG-like helicase is a RIG-I PRR. 
     
     
         9 . The composition of  claim 1 , wherein the PRR is a Toll-like receptor (TLR) PRR. 
     
     
         10 . The composition of  claim 1 , wherein the chimeric protein comprises a cytoplasmic region from a TLR PRR. 
     
     
         11 . The composition of  claim 10 , wherein the chimeric protein comprises a TIR domain. 
     
     
         12 . The composition of  claim 10 , wherein the chimeric protein consists essentially of a TIR domain. 
     
     
         13 . The composition of  claim 1 , wherein the chimeric protein comprises an adapter that binds to a PRR. 
     
     
         14 . The composition of  claim 2 , wherein the chimeric protein comprises an adapter that binds to a PRR. 
     
     
         15 . The composition of  claim 13 , wherein the adaptor is selected from the group consisting of MyD88, TRIF/TICAM-1, TIRAM/ICAM-2, MAL/TIRAP, TIR and CARD. 
     
     
         16 . The composition of  claim 1 , wherein the membrane targeting region is a myristoylation targeting region. 
     
     
         17 . The composition of  claim 2 , wherein the CD40 cytoplasmic polypeptide region is encoded by a polynucleotide sequence in SEQ ID NO: 1. 
     
     
         18 . The composition of  claim 1 , wherein the ligand is a small molecule. 
     
     
         19 . The composition of  claim 18 , wherein the ligand is a dimeric FK506 or a dimeric FK506 analog. 
     
     
         20 . The composition of  claim 18 , wherein the ligand is AP1903. 
     
     
         21 . The composition of  claim 1 , wherein the nucleic acid is contained within a viral vector. 
     
     
         22 . The composition of  claim 21 , wherein the viral vector is an adenoviral vector. 
     
     
         23 . The composition of  claim 1 , wherein the nucleic acid comprises a promoter sequence operably linked to the polynucleotide sequence.