Productive activation of T cells requires integration of two signals: one, antigen specific, provided by the T cell receptor; and a second signal activated by the engagement of co-stimulatory receptors. Anergy, one of the mechanisms that accounts for establishment of peripheral tolerance, is evoked by an unbalanced activation of T cells through their antigen receptor without simultaneous engagement of co-stimulatory receptors. In this situation, T cells not only do not start a proliferative response, but they become unable to produce IL-2 and proliferate when re-stimulated with antigen in the presence of co-stimulation. Anergic stimuli produce a preferential activation of calcium signaling relative to other co-stimulation dependent signaling pathways. Under these conditions, members of the NFAT family of transcription factors are activated in the absence of their main transcriptional copartner, AP-1, directing the expression of a specific set of genes characteristic of the anergic response. We now propose to determine the mechanisms and consequences of the induction of anergy-associated programs of gene expression. The specific questions we will address are: 1) How is the expression of anergy-associated genes regulated? 2) What are the consequences of the activation of those genes? 3) Is the expression of anergy-associated genes able to induce T cell tolerance? To achieve these goals we propose three specific aims: 1) to study the nature of the NFAT complexes found on the promoters of those genes, differentiating them from those that bind to genes expressed during a productive immune response; 2) To determine the role of specific anergy-associated genes in the induction of T cell tolerance; and 3) to characterize the induction and maintenance of T cell anergy and its role in peripheral tolerance in a mouse model that constitutively activates the expression of anergy-associated genes. Defining the mechanisms that control the activation of a transcriptional program specific of T cell anergy and the molecular pathways affected by the expression of those genes should prove valuable to understand how immune tolerance is established and to define targets that will help design new therapeutic approaches for autoimmune diseases, organ transplant rejection and allergy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059738-05
Application #
7414748
Study Section
Immunobiology Study Section (IMB)
Program Officer
Lapham, Cheryl K
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$349,511
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Ames, Rachel Y; Ting, Li-Min; Gendlina, Inessa et al. (2017) The Transcription Factor NFAT1 Participates in the Induction of CD4+ T Cell Functional Exhaustion during Plasmodium yoelii Infection. Infect Immun 85:
Bandyopadhyay, Sanmay; Quinn, Thomas J; Scandiuzzi, Lisa et al. (2016) Low-Intensity Focused Ultrasound Induces Reversal of Tumor-Induced T Cell Tolerance and Prevents Immune Escape. J Immunol 196:1964-76
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Bandyopadhyay, Sanmay; Valdor, Rut; Macian, Fernando (2014) Tle4 regulates epigenetic silencing of gamma interferon expression during effector T helper cell tolerance. Mol Cell Biol 34:233-45
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Valdor, Rut; Macian, Fernando (2013) Induction and stability of the anergic phenotype in T cells. Semin Immunol 25:313-20

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