The thymus generates a vast excess of cells that fail to complete maturation and die in situ. This is a result of the processes of beta-selection, positive selection, and negative selection that place stringent controls on various stages of T cell development. Both beta-selection and positive selection are cell differentiation events that result in stable changes in gene expression. There is still much to learn about the molecular control of gene expression during these critical developmental transitions. We have recently identified a gene encoding a novel regulator of thymocyte selection we termed TOX (thymocyte selection associated HMG-box protein). As its name implies, TOX is a member of the HMG-box superfamily of nuclear proteins. HMG-box proteins are architectural factors that bind DNA and regulate formation of mutiprotein transcriptional regulatory complexes and/or are involved in regulating chromatin accessibility. TOX also belongs to a small conserved subfamily of HMG-box proteins. Expression of TOX in the thymus is tightly regulated and is associated with both beta-selection and positive selection. Data indicate that expression of TOX in the thymus of transgenic mice is sufficient to initiate both of these differentiation processes. This includes promotion of CD8 T cell lineage commitment at the expense of CD4 lineage commitment. We propose to further investigate the biological functions of this novel nuclear protein. Specific approaches are outlined to; determine the expression of TOX and family members during lymphocyte development, analyze biochemical characteristics of TOX, determine subcellular and intranuclear localization of the protein, identify signaling pathways that regulate its expression, perform a structure/function analysis of various forms of TOX in vitro and in vivo, produce TOX deficient mice, identify other proteins that interact with domains of TOX and identify gene targets for this nuclear protein in the context of positive selection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054977-02
Application #
6828313
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$422,325
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Harly, Christelle; Cam, Maggie; Kaye, Jonathan et al. (2018) Development and differentiation of early innate lymphoid progenitors. J Exp Med 215:249-262
Page, Nicolas; Klimek, Bogna; De Roo, Mathias et al. (2018) Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells. Immunity 48:937-950.e8
Seehus, Corey R; Kadavallore, Asha; Torre, Brian de la et al. (2017) Alternative activation generates IL-10 producing type 2 innate lymphoid cells. Nat Commun 8:1900
Seehus, Corey; Kaye, Jonathan (2016) In vitro Differentiation of Murine Innate Lymphoid Cells from Common Lymphoid Progenitor Cells. Bio Protoc 6:
Seehus, Corey R; Kaye, Jonathan (2015) The Role of TOX in the Development of Innate Lymphoid Cells. Mediators Inflamm 2015:243868
Kaye, Jonathan (2015) ILC development: TCF-1 reporting in. Nat Immunol 16:1011-2
Seehus, Corey R; Aliahmad, Parinaz; de la Torre, Brian et al. (2015) The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nat Immunol 16:599-608
Aliahmad, Parinaz; Seksenyan, Akop; Kaye, Jonathan (2012) The many roles of TOX in the immune system. Curr Opin Immunol 24:173-7
Aliahmad, Parinaz; Kadavallore, Asha; de la Torre, Brian et al. (2011) TOX is required for development of the CD4 T cell lineage gene program. J Immunol 187:5931-40
Aliahmad, Parinaz; de la Torre, Brian; Kaye, Jonathan (2010) Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat Immunol 11:945-52

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