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 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.

Abstract: This invention demonstrates that KRC molecules have multiple important functions as modulating agents in regulating a wide variety of cellular processes including: inhibiting NFkB transactivation, increasing TNF-alpha induced apoptosis, inhibiting JNK activation, inhibiting endogenous TNF-alpha expression, promoting immune cell proliferation and immune cell activation (e.g., in Th1 cells and/or Th2), activating IL-2 expression e.g., by activating the AP-1 transcription factor, and increasing actin polymerization. The present invention also demonstrates that KRC interacts with TRAF. Furthermore, the present invention demonstrates that KRC physically interacts with the c-Jun component of AP-1 to control its degradation. The present invention also demonstrates that KRC is downstream of several lymphocyte membrane receptors, including TNFR, TCR and TGF?R. Upon TNFR signaling, KRC associates with the adaptor protein TRAF2 to inhibit NFKB and JNK-dependent gene expression.

Abstract: The instant invention is based, at least in part, on the dentification of a mechanism by which T-bet modulates IL2 production. The present invention pertains to methods of identifying agents that modulate the kinase-mediated interaction of T-bet with RelA, as well as methods of use therefore.

Abstract: Methods for modulating production of a T helper type 2 (Th2)-associated cytokine, in particular interleukin-4, by modulating the activity of a transcription factor, in particular the proto-oncoprotein c-Maf, that regulates expression of the Th2-associated cytokine gene are disclosed. 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. The methods of the invention can further involve use of agents that modulate the activity of additional transcription factors that contribute to the regulation of Th1- or Th2-associated cytokines, such as a Nuclear Factor of Activated T cells (NF-AT) protein and/or an AP-1 family protein. Compositions for modulating Th2-associated cytokine production, recombinant expression vectors and host cells, as well as screening assays to identify agents that modulate c-Maf activity, are also disclosed.

Abstract: The instant invention is based, at least in part, on the identification of a mechanism by which T-bet directly modulates Th2 cytokine production. The present invention pertains to methods of identifying agents that modulate the Tec kinase-mediated interaction of T-bet with GATA-3, as well as methods of use therefore.

Abstract: Tumor cells modified to express a T cell costimulatory molecule are disclosed. In one embodiment, the costimulatory molecule is a CD28/CTLA4 ligand, preferably a B lymphocyte antigen B7. The tumor cells of the invention can be modified by transfection with nucleic acid encoding a T cell costimulatory molecule, by using an agent which induces or increases expression of a T cell costimulatory molecule on the tumor cell surface or by coupling a T cell costimulatory molecule to the tumor cell surface. Tumor cells further modified to express MHC class I and/or class II molecules or in which expression of an MHC associated protein, the invariant chain, is inhibited are also disclosed. The modified tumor cells of the invention can be used in methods for treating-a patient with a tumor, preventing or inhibiting metastatic spread of a tumor or preventing or inhibiting recurrence of a tumor.

Abstract: Isolated nucleic acid molecules encoding T-bet, and isolated T-bet proteins, are provided. The invention further provides antisense nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced and non-human transgenic animals carrying a T-bet transgene. The invention further provides T-bet fusion proteins and anti-T-bet antibodies. Methods of using the T-bet compositions of the invention are also disclosed, including methods for detecting T-bet activity in a biological sample, methods of modulating T-bet activity in a cell, and methods for identifying agents that modulate the activity of T-bet.

Abstract: The invention demonstrates that NFATp and NFAT4 are required for the control of lymphocyte homeostasis and act as selective repressors of Th2 cells. The invention provides mice deficient in both NFATp and NFAT4 that exhibit a phenotype characteristic of increased Th2 cell activity. Methods for identifying modulators of Th2 cell activity, using either cells deficient in both NFATp and NFAT4, mice deficient in both NFATp and NFAT4, or indicator compositions containing both NFATp and NFAT4, are provided. Methods of regulating Th2 cell activity using agents that modulate the activity of NFATp and NFAT4 are also provided. Methods for diagnosing disorders associated with aberrant Th2 cell activity, by assessing changes in NFATp and/or NFAT4 expression, are also provided.

Abstract: The invention provides methods and compositions for modulating the expression, processing, post-translational modification, stability and/or activity of XBP-1 protein, or a protein in a signal transduction pathway involving XBP-1 to treat metabolic disorders, e.g., type II diabetes. The present invention also pertains to methods for identifying compounds that modulate the expression, processing, post-translational modification, and/or activity of XBP-1 protein or a molecule in a signal transduction pathway involving XBP-1.

Abstract: This invention demonstrates that KRC molecules have multiple important functions as modulating agents in regulating a wide variety of cellular processes including: inhibiting NFkB transactivation, increasing TNF-alpha induced apoptosis, inhibiting JNK activation, inhibiting endogenous TNF-alpha expression, promoting immune cell proliferation and immune cell activation (e.g., in Th1 cells), activating IL-2 expression e.g., by activating the AP-1 transcription factor, and increasing actin polymerization. The present invention also demonstrates that KRC interacts with TRAF. Furthermore, the present invention demonstrates that KRC physically interacts with the c-Jun component of AP-1 to control its degradation Methods for identifying modulators of KRC activity are provided. Methods for modulating an immune response using agents that modulate KRC activity are also provided.

Abstract: Isolated nucleic acid molecules encoding human c-Maf, and isolated c-Maf proteins, are provided. The invention further provides antisense nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced and non-human transgenic animals carrying a human c-Maf transgene. The invention further provides human c-Maf fusion proteins and anti-human c-Maf antibodies. Methods of using the human c-maf compositions of the invention are also disclosed, including methods for detecting human c-Maf activity in a biological sample, methods of modulating human c-Maf activity in a cell, and methods for identifying agents that modulate the activity of human c-Maf.