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Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease

Award Number: R01DK105550
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Inflammatory diseases are often driven by inappropriate responses of effector CD4 T cells (Teff). IL17, IFNγ, or dual-producing polyfunctional effector Th1, Th17, or Th17.1 T cells can become imbalanced with suppressive Treg CD4 T cells in a variety of disease settings, including inflammatory bowel diseases (IBD). A key therapeutic objective in efforts to shift the immunologic balance towards tolerance, therefore, is to selectively inhibit Teff and promote Treg. We have shown that Teff and Treg subsets utilize different metabolic programs that represent fundamental features of T cell biology. Here we explore one carbon (1C) metabolism and related microenvironmental factors to modulate CD4 T cells in inflammatory diseases. 1C metabolism integrates multiple nutrient inputs to provide intermediates for de novo methionine and purine synthesis and is commonly targeted with anti-folate drugs. An in vivo CRISPR screen of primary T cells in IBD with a 1C metabolism enzyme-focused gRNA library identified the mitochondrial enzyme Methylene-tetrahydrofolate Dehydrogenase 2 (MTHFD2) as conditionally essential for effector T cell proliferation and inflammation. MTHFD2 was upregulated in T cells a variety of inflammatory conditions and while MTHFD2-deficiency impaired Teff, MTHFD-deficient Treg had increased FoxP3 expression in both mouse and human T cells. Consistent with a role as a metabolic checkpoint on inflammation, MTHFD2-deficiency protected against IBD and other inflammatory diseases. Mechanistically, MTHFD2 inhibition suppressed mTORC1 activity, possibly through reduced methionine and/or interrupted purine synthesis. Importantly, local nutrients play key roles in 1C metabolism and T cell fate. To quantify T cell access to nutrients in vivo, we established Positron Emission Tomography (PET) tracer-based methods to directly image and measure nutrient uptake in vivo. These studies showed a sharp increase in T cell glucose uptake in inflammation. In addition, IBD is often associated with folate-deficiency. The effects of dietary folate on T cell 1C metabolism, mTORC1 signaling, and fate, however, are unclear. Because inflammation is associated with fevers and enzymes are temperature-dependent, we also tested fever conditions on T cell metabolism. We found fever led to increased cytokine production from Teff and mitochondrial Reactive Oxygen Species (ROS) specifically in Th1 cells that, surprisingly, led to Tp53-dependent apoptosis. These findings support the hypothesis that 1C metabolism is limiting and serves as a metabolic checkpoint to integrate local nutrients and physical conditions through MTHFD2 and mTORC1 signaling to provide new immunometabolic targets to modulate effector and regulatory T cells. To test this, we will: (1) Test the role and mechanism of MTHFD2 as a limiting enzyme in methionine and nucleotide synthesis essential for mTORC1 signaling and effector T cells; and (2) Determine how nutrient and microenvironmental factors such as folate and fever influence effector and regulatory T cell metabolism and inflammation. These studies will test MTHFD2 and identify new immunometabolic mechanisms and targets that contribute to or may be exploited to treat inflammatory disease.


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: 2024 ( Subtotal = $390,666 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	1/19/2024	NON-COMPETING CONTINUATION	$366,251
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	12	5/15/2024	NON-COMPETING CONTINUATION	$24,415
2024	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	1/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,666

Issue Date FY: 2023 ( Subtotal = $407,341 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	2/24/2023	COMPETING CONTINUATION	$407,341
2023	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	2/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $407,341

Issue Date FY: 2022 ( Subtotal = $381,300 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/25/2022	NON-COMPETING CONTINUATION	$381,300
														Subtotal = $381,300

Issue Date FY: 2021 ( Subtotal = $381,330 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/30/2021	NON-COMPETING CONTINUATION	$381,330
														Subtotal = $381,330

Issue Date FY: 2020 ( Subtotal = $389,294 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	3/5/2020	NON-COMPETING CONTINUATION	$389,294
														Subtotal = $389,294

Issue Date FY: 2019 ( Subtotal = $389,203 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/8/2019	COMPETING CONTINUATION	$389,203
2019	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/1/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $389,203

Issue Date FY: 2018 ( Subtotal = $377,741 )
2018	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/8/2018	NON-COMPETING CONTINUATION	$339,966
2018	2018	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	5/7/2018	NON-COMPETING CONTINUATION	$37,775
														Subtotal = $377,741

Issue Date FY: 2017 ( Subtotal = $377,741 )
2017	2017	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	6/15/2017	NON-COMPETING CONTINUATION	$37,775
2017	2017	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	3/23/2017	NON-COMPETING CONTINUATION	$339,966
2017	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	1/5/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$9,512
2017	2015	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/5/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$9,512
														Subtotal = $377,741

Issue Date FY: 2016 ( Subtotal = $379,166 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	3	5/10/2016	NON-COMPETING CONTINUATION	-$376,770
2016	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	4	5/16/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$379,054
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	3	4/6/2016	NON-COMPETING CONTINUATION	$376,770
2016	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	11/5/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$282,554
2016	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/29/2015	NEW	-$282,442
2016	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	1/7/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$282,554
2016	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	1/12/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$282,554
														Subtotal = $379,166

Issue Date FY: 2015 ( Subtotal = $393,554 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/6/2015	NEW	$393,554
														Subtotal = $393,554

Grand Total All Awards = $3,867,336

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Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease

Award Number: R01DK105550

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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