The long-term goal of this proposal is to understand the molecular basis for lymphocyte anergy and tolerance. Its specific objective is to investigate the role of NFAT, a Ca2+-activated transcription factor, in these processes. We have shown that NFAT can turn on two opposing gene expression programmes in T cells: a programme of productive activation defined by upregulation of genes encoding cytokines, chemokines and cell surface receptors, whose regulatory regions typically contain composite binding sites for NFAT and its transcriptional partner AP-1 (Fos-Jun); and a non-overlapping programme of negative regulation, induced by NFAT in the absence of AP-1, whose functional consequence is to render T cells """"""""anergic"""""""", i.e. unresponsive to subsequent stimulation through the TCP. This application will follow up on these earlier findings.
Aim 1 is to systematically identify potential targets and effectors of the Ca2+-induced negative regulatory programme, and test whether they affect T cell responses or influence anergy induction.
Aim 2 is to investigate the relation between NFAT and regulatory T cells. In collaboration with a structural laboratory, we have shown that FoxP proteins bind cooperatively with NFAT on composite NFAT: AP-1 sites. We will examine the role of this interaction in the function of regulatory T cells.
Aim 3 is to define the contribution of NFAT, its AP-1 and FoxP partners and its target/ effector proteins in a selected model of autoimmunity in mice. These studies are important from a clinical perspective: being able to manipulate T cell tolerance is valuable in almost every immunological setting including transplant medicine, asthma and allergy, and diverse manifestations of autoimmune disease.
|Keller, Tracy L; Zocco, Davide; Sundrud, Mark S et al. (2012) Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol 8:311-7|
|Bandukwala, Hozefa S; Wu, Yongqing; Feuerer, Markus et al. (2011) Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells. Immunity 34:479-91|
|Sundrud, Mark S; Koralov, Sergei B; Feuerer, Markus et al. (2009) Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324:1334-8|
|Oh-hora, Masatsugu; Rao, Anjana (2009) The calcium/NFAT pathway: role in development and function of regulatory T cells. Microbes Infect 11:612-9|
|Picard, Capucine; McCarl, Christie-Ann; Papolos, Alexander et al. (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971-80|
|Koh, Kian Peng; Sundrud, Mark S; Rao, Anjana (2009) Domain requirements and sequence specificity of DNA binding for the forkhead transcription factor FOXP3. PLoS One 4:e8109|
|Soto-Nieves, Noemi; Puga, Irene; Abe, Brian T et al. (2009) Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance. J Exp Med 206:867-76|
|Oh-Hora, Masatsugu; Yamashita, Megumi; Hogan, Patrick G et al. (2008) Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat Immunol 9:432-43|
|Puga, Irene; Rao, Anjana; Macian, Fernando (2008) Targeted cleavage of signaling proteins by caspase 3 inhibits T cell receptor signaling in anergic T cells. Immunity 29:193-204|
|Sundrud, Mark S; Rao, Anjana (2007) New twists of T cell fate: control of T cell activation and tolerance by TGF-beta and NFAT. Curr Opin Immunol 19:287-93|
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