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Investigating the role of TET deficiency in promoting T cell expansion and inflammation

Award Number: R01AI128589
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/07/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Investigating the role of TET deficiency in promoting T cell expansion and inflammation - Abstract DNA cytosine methylation (hereafter, DNA methylation) has a critical role in cell lineage specification as well as suppression of repetitive and transposable elements in the genome. DNA methyltransferases attach a methyl group to generate 5-methylcytosine (5mC); TET methylcytosine dioxygenases cause DNA demethylation by oxidizing the methyl group of 5mC to 5-hydroxymethylcytosine (5hmC) and beyond. We have shown that TET- deficient cell types display not only the expected increase in DNA methylation at promoters and enhancers, but also a paradoxical decrease in DNA methylation in heterochromatic regions of the genome. The consequences of these molecular features remain to be understood, but similar alterations in genome-wide DNA methylation patterns have been observed in cancer and aging. By studying the phenotypes of several mouse strains in which Cre recombinase was expressed either inducibly or developmentally in immune/ hematopoietic cell types, we showed that deletion of two or more Tet genes skewed cell lineage commitment in the relevant cell type, in a manner that correlated with changes in cell lineage commitment. More striking phenotypes, however, were that Tet2/3 fl/fl CD4Cre mice displayed massive TCR- dependent expansion of iNKT cells; and that Tet2/3 fl/fl Foxp3Cre mice developed a dominant proinflammatory phenotype observed in heterozygous female mice, in mixed bone marrow chimaeras, and in immunocompetent recipients injected with total CD4+ T cells from Tet2/3 fl/fl Foxp3Cre mice. This phenotype differs markedly from that observed in heterozygous Foxp3+/- females and in immunocompetent mice injected with Foxp3-deficient cells, which do not develop disease. In Aim 1, we will address the mechanisms underlying the striking expansion of Tet2/3-deficient iNKT cells by using adoptive transfer approaches in vivo and recently-developed cell culture systems that recapitulate the expansion in vitro. In Aim 2, we will ask whether the dominant autoimmune/ inflammatory phenotype of Tet2/3-deficient T regulatory cells requires, directly or indirectly, the decreased DNA methylation in heterochromatin observed in every TET-deficient cell type examined so far. Decreased DNA methylation in heterochromatin results in “heterochromatin dysfunction”, an aberrant cellular condition linked to autoimmune/ inflammatory disorders, cancer, aging, and neurodegenerative diseases, that stems from aberrant expression of transposable elements (TEs) and resulting DNA damage. DNA damage provokes “sterile inflammation”: activation of innate immune sensing pathways for RNA and DNA with consequent upregulation of type I interferons, interferon-induced genes and proinflammatory cytokines (e.g. IL-1b, IL-6, IFNg, IL-17) Our proposed experiments will add to our knowledge of how TET proteins influence T cell expansion and T regulatory function. More broadly, they will enhance our general understanding of the links connecting TET deficiency and TE expression with autoimmune/ inflammatory diseases, clonal hematopoiesis, a premalignant syndrome of older individuals associated with inflammation and cardiovascular disease, and cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,098,000 )
2025	2025	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	9	6/10/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,098,000
2025	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	6/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,098,000

Issue Date FY: 2024 ( Subtotal = $679,237 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	8	7/5/2024	NON-COMPETING CONTINUATION	$0
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	003	8	8/9/2024	SUPPLEMENT FOR EXPANSION	$130,237
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	8	5/27/2024	NON-COMPETING CONTINUATION	$549,000
2024	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	2/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $679,237

Issue Date FY: 2023 ( Subtotal = $549,000 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	5/16/2023	NON-COMPETING CONTINUATION	$549,000
														Subtotal = $549,000

Issue Date FY: 2022 ( Subtotal = $549,000 )
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	6/7/2022	COMPETING CONTINUATION	$549,000
														Subtotal = $549,000

Issue Date FY: 2021 ( Subtotal = $450,000 )
2021	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	5/25/2021	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2020 ( Subtotal = $450,000 )
2020	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	5/18/2020	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2019 ( Subtotal = $450,000 )
2019	2019	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	5/14/2019	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2018 ( Subtotal = $630,000 )
2018	2018	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	6/27/2018	NON-COMPETING CONTINUATION	$180,000
2018	2018	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	5/23/2018	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $630,000

Issue Date FY: 2017 ( Subtotal = $450,000 )
2017	2017	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	6/7/2017	NEW	$450,000
														Subtotal = $450,000

Grand Total All Awards = $5,305,237

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Investigating the role of TET deficiency in promoting T cell expansion and inflammation

Award Number: R01AI128589

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/07/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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