Methods for regulating T cell subsets by modulating transcription factor activity

Abstract

Methods for modulating production of a T helper type 2 (Th2)-associated cytokine, in particular interleukin-4, by modulating the activity of one or more transcription factors that cooperate with NF-AT family proteins to regulate expression of a Th2-associated cytokine gene are disclosed. In one embodiment, the activity of a maf family protein (e.g., c-Maf or a small maf protein, such as p18) is modulated. In another embodiment, the activity of a protein that interacts with an NF-AT family protein (e.g., NIP45) is modulated. Combination methods, for example wherein the activities of a maf family protein and an NF-AT protein are modulated or the activities of a maf protein and and NF-AT-interacting protein are modulated, are also encompassed by the invention. Methods for modulating development of T helper type 1 (Th1) or T helper type 2 (Th2) subsets in a subject using agents that modulate transcription factor activity are also disclosed.

We claim:  
     
         1 . A method for modulating production of a T helper type 2 (Th2)-associated cytokine by a cell comprising contacting the cell with an agent that modulates the expression or activity of a transcription factor such that production of the Th2-associated cytokine by a cell is modulated, wherein the transcription factor cooperates with a Nuclear Factor of Activated T cells (NF-AT) family protein to regulate expression of the Th2-associated cytokine gene.  
     
     
         2 . The method of  claim 1 , wherein the agent acts intracellularly to modulate the expression or activity of the transcription factor.  
     
     
         3 . The method of  claim 1 , wherein production of a Th2-associated cytokine by the cell is stimulated.  
     
     
         4 . The method of  claim 3 , wherein the cell is a T helper type 1 (Th1) cell, a B cell or a nonlymphoid cell.  
     
     
         5 . The method of  claim 1 , wherein production of a Th2-associated cytokine by the cell is inhibited.  
     
     
         6 . The method of  claim 1 , wherein the Th2-associated cytokine is interleukin-4.  
     
     
         7 . The method of  claim 1 , wherein the transcription factor is a Th2-specific transcription factor.  
     
     
         8 . The method of  claim 1 , wherein the transcription factor is a maf family protein.  
     
     
         9 . The method of  claim 1  wherein the transcription factor interacts with an NF-AT family protein.  
     
     
         10 . The method of  claim 1 , wherein the cell is contacted with at least one additional agent that modulates the activity of at least one additional transcription factor that contributes to the regulation of the Th2-associated cytokine gene.  
     
     
         11 . The method of  claim 10 , wherein the at least one additional transcription factor is selected from the group consisting of NF-AT family proteins, NF-AT-interacting proteins, maf family proteins and AP-1 family proteins.  
     
     
         12 . The method of  claim 1 , further comprising administering the cell to a subject to thereby modulate development of T helper type 1 (Th1) or T helper type 2 (Th2) cells in a subject.  
     
     
         13 . A method for modulating production of a T helper type 2 (Th2)-associated cytokine by a cell comprising contacting the cell with an agent that modulates the expression or activity of a transcription factor such that production of the Th2-associated cytokine by a cell is modulated, wherein the transcription factor is a maf family protein.  
     
     
         14 . The method of  claim 13 , wherein the maf family protein is c-Maf.  
     
     
         15 . The method of  claim 13 , wherein the maf family protein is a small maf protein.  
     
     
         16 . The method of  claim 15 , wherein the small maf protein is p18.  
     
     
         17 . The method of  claim 13 , wherein the agent is a nucleic acid molecule encoding a maf family protein, wherein the nucleic acid molecule is introduced into the cell in a form suitable for expression of the maf family protein in the cell.  
     
     
         18 . The method of  claim 13 , wherein the agent is an intracellular binding molecule.  
     
     
         19 . The method of  claim 13 , wherein the cell is contacted with at least one additional agent that modulates the activity of at least one additional transcription factor that contributes to the regulation of the Th2-associated cytokine gene.  
     
     
         20 . The method of  claim 19 , wherein the at least one additional transcription factor is selected from the group consisting of NF-AT family proteins, NF-AT-interacting proteins, other maf family proteins and AP-1 family proteins.  
     
     
         21 . The method of  claim 13 , further comprising administering the cell to a subject to thereby modulate development of T helper type 1 (Th1) or T helper type 2 (Th2) cells in a subject.  
     
     
         22 . A method for modulating production of a T helper type 2 (Th2)-associated cytokine by a cell comprising contacting the cell with an agent that modulates the expression or activity of a transcription factor such that production of the Th2-associated cytokine by a cell is modulated, wherein the transcription factor interacts with a Nuclear Factor of Activated T cells (NF-AT) family protein.  
     
     
         23 . The method of  claim 22 , wherein the transcription factor interacts with the Rel Homology Domain of an NF-AT family protein.  
     
     
         24 . The method of  claim 23 , wherein the transcription factor is NIP45.  
     
     
         25 . The method of  claim 22 , wherein the agent is a nucleic acid molecule encoding the transcription factor, wherein the nucleic acid molecule is introduced into the cell in a form suitable for expression of the transcription factor in the cell.  
     
     
         26 . The method of  claim 22 , wherein the agent is an intracellular binding molecule.  
     
     
         27 . The method of  claim 22 , wherein the cell is contacted with at least one additional agent that modulates the activity of at least one additional transcription factor that contributes to the regulation of the Th2-associated cytokine gene.  
     
     
         28 . The method of  claim 27 , wherein the at least one additional transcription factor is selected from the group consisting of NF-AT family proteins, other NF-AT-interacting proteins, maf family proteins and AP-1 family proteins.  
     
     
         29 . The method of  claim 22 , further comprising administering the cell to a subject to thereby modulate development of T helper type 1 (Th1) or T helper type 2 (Th2) cells in a subject.  
     
     
         30 . A method for stimulating production of a T helper type 2 (Th2)-associated cytokine by a cell comprising introducing into the cell a nucleic acid molecule encoding a transcription factor such that production of the Th2-associated cytokine by a cell is stimulated, wherein the transcription factor cooperates with a Nuclear Factor of Activated T cells (NF-AT) family protein to regulate expression of the Th2-associated cytokine gene, the nucleic acid molecule being in a form suitable for expression of the transcription factor in the cell.  
     
     
         31 . The method of  claim 30 , wherein the cell is a T helper type 1 (Th1) cell, a B cell or a nonlymphoid cell.  
     
     
         32 . The method of  claim 30 , wherein the transcription factor is a Th2-specific transcription factor.  
     
     
         33 . The method of  claim 30 , wherein the transcription factor is a maf family protein.  
     
     
         34 . The method of  claim 33 , wherein the maf family protein is c-Maf.  
     
     
         35 . The method of  claim 30 , wherein the transcription factor interacts with an NF-AT family protein.  
     
     
         36 . The method of  claim 35 , wherein the transcription factor is NIP45.  
     
     
         37 . The method of  claim 30 , wherein at least one additional nucleic acid molecule encoding at least one additional transcription factor that contributes to the regulation of the Th2-associated cytokine gene is introduced into the cell.  
     
     
         38 . The method of  claim 37 , wherein the at least one additional transcription factor is selected from the group consisting of NF-AT family proteins, NF-AT-interacting proteins, maf family proteins and AP-1 family proteins.  
     
     
         39 . The method of  claim 30 , further comprising administering the cell to a subject to thereby modulate development of T helper type 1 (Th1) or T helper type 2 (Th2) cells in a subject.  
     
     
         40 . A method for inhibiting production of a T helper type 2 (Th2)-associated cytokine by a cell comprising introducing into the cell a nucleic acid molecule encoding a small maf protein such that production of the Th2-associated cytokine by a cell is inhibited, the nucleic acid molecule being in a form suitable for expression of the small maf protein in the cell.  
     
     
         41 . The method of  claim 40 , wherein the small maf protein is p18.  
     
     
         42 . The method of  claim 40 , wherein the small maf protein is selected from the group consisting of mafK, mafF and mafG.  
     
     
         43 . A method for modulating development of T helper type 1 (Th1) or T helper type 2 (Th2) cells in a subject comprising administering to the subject an agent that modulates the expression or activity of transcription factor such that development of Th1 or Th2 cells in the subject is modulated, wherein the transcription factor cooperates with a Nuclear Factor of Activated T cells (NF-AT) family protein to regulate expression of the Th2-associated cytokine gene.  
     
     
         44 . The method of  claim 43 , wherein the agent acts intracellularly to modulate the expression or activity of the transcription factor.  
     
     
         45 . The method of  claim 43 , wherein the transcription factor is a Th2-specific transcription factor.  
     
     
         46 . The method of  claim 43 , wherein the transcription factor is a maf family protein.  
     
     
         47 . The method of  claim 46 , wherein the maf family protein is c-Maf.  
     
     
         48 . The method of  claim 47 , wherein the maf family protein is a small maf protein.  
     
     
         49 . The method of  claim 43 , wherein the transcription factor interacts with an NF-AT family protein.  
     
     
         50 . The method of  claim 49 , wherein the transcription factor is NIP45.  
     
     
         51 . The method of  claim 43 , wherein at least one additional agent that modulates the activity of at least one additional transcription factor that contributes to the regulation of the Th2-associated cytokine gene is administered to the subject.  
     
     
         52 . The method of  claim 51 , wherein the at least one additional transcription factor is selected from the group, consisting of NF-AT family proteins, NF-AT-interacting proteins, maf family proteins and AP-1 family proteins.