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Intestinal CD4 T cell responses to dietary and microbial antigens

Award Number: R01DK093674
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2013
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Intestinal CD4 T cell responses to dietary and microbial antigens - Project Summary The highly specialized intestinal immune system is charged with maintaining tolerance to harmless stimuli from commensal bacteria and food, while providing protective immunity against pathogens. Dysregulation of this critical balance can lead to inflammatory bowel disease, food allergy, or increased susceptibility to enteric pathogens. CD4+ T cells are key players in intestinal homeostasis, finely tuning responses at the level of antigen recognition and functional differentiation. In the intestinal epithelium (IE) and underlying lamina propria (LP), tissue adapted pro-inflammatory (ie. Th17, Th1) and regulatory (Treg) and intraepithelial (CD8aa+ CD4IEL) CD4+ T cells coordinate immunity and tolerance to diverse intestinal stimuli. Nevertheless, it remains to be defined how TCR repertoire and its specificity translate to function of both LP and IELs in response to microbial antigens. Additionally, very little is known about the characteristics of dietary antigen-specific intestinal T cells. Oral tolerance, a critical mechanism of gut homeostasis whereby oral administration of antigen results in both local and systemic tolerance to that antigen, is known to depend on Tregs. However, the clonal dynamics of polyclonal T cell responses in the setting of tolerance remain unclear. Finally, outside the context of immunization or allergy, T cells that specifically recognize food protein have yet to be identified. Based on data recently published as well as preliminary data obtained during the current funding cycle, we hypothesize that tissue cues combined with TCR-driven signals from commensal microbes and food dictate intestinal T cell functional differentiation in steady state, while disruption of normal T cell responses by infections or allergens results in inappropriate clonal dynamics including expansion of pathological T cells. Aim 1 will define how stimulation by microbiota or enteric viruses impact TCR repertoire and functional differentiation of intestinal CD4 T cells. Aim 2 will characterize the role of dietary antigens in the context of tolerance, enteric infections, or food allergy, affect TCR repertoire and functional differentiation of intestinal CD4 T cells. We combine single cell transcriptomics with a novel fate- mapping strategy to selectively label peripheral T cells that are recruited to the intestine under various microbial and dietary challenges. A recently developed LIPSTIC tool that allows intestinal epithelial cells (IECs) labeling of interacting cells will be utilized to define potential mechanisms of IEL recruitment/expansion in response to nonself stimuli. Recently generated murine strains with fixed TCR Vb chain, or that carry microbiota-specific TCRs, combined with complementary tetramer and gnotobiotic strategies will be used to specifically track and define recognition properties during T cell migration and differentiation in the gut. Novel “super-tetramer” and dietary manipulations, combined with inflammatory challenges will be used to define food antigen-specific T cells during steady state and how intestinal CD4+ T cell responses to dietary antigen are altered in a food allergic or infection context. By combining these innovative approaches and concepts in mucosal immunology, this proposal will help better defining the role of nonself antigen stimulation in T cell repertoire and function in the intestine.


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 = $597,872 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	6/11/2025	NON-COMPETING CONTINUATION	$59,787
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	1/23/2025	NON-COMPETING CONTINUATION	$538,085
														Subtotal = $597,872

Issue Date FY: 2024 ( Subtotal = $573,958 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	5/14/2024	NON-COMPETING CONTINUATION	$35,873
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	12/13/2023	NON-COMPETING CONTINUATION	$538,085
														Subtotal = $573,958

Issue Date FY: 2023 ( Subtotal = $597,872 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	1/9/2023	NON-COMPETING CONTINUATION	$597,872
														Subtotal = $597,872

Issue Date FY: 2022 ( Subtotal = $615,247 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	5/6/2022	COMPETING CONTINUATION	$2,814
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	12/23/2021	COMPETING CONTINUATION	$615,247
2022	2021	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	5/6/2022	NON-COMPETING CONTINUATION	-$2,814
														Subtotal = $615,247

Issue Date FY: 2021 ( Subtotal = $541,324 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	12/7/2020	NON-COMPETING CONTINUATION	$487,191
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	2/3/2021	NON-COMPETING CONTINUATION	$54,133
														Subtotal = $541,324

Issue Date FY: 2020 ( Subtotal = $541,324 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	2/10/2020	NON-COMPETING CONTINUATION	$54,133
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	12/11/2019	NON-COMPETING CONTINUATION	$487,191
														Subtotal = $541,324

Issue Date FY: 2019 ( Subtotal = $541,324 )
2019	2019	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	12/11/2018	NON-COMPETING CONTINUATION	$541,324
														Subtotal = $541,324

Issue Date FY: 2018 ( Subtotal = $541,324 )
2018	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	11/24/2017	COMPETING CONTINUATION	$541,324
2018	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/23/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $541,324

Issue Date FY: 2017 ( Subtotal = $368,663 )
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/14/2017	NON-COMPETING CONTINUATION	$36,867
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/22/2016	NON-COMPETING CONTINUATION	$331,796
														Subtotal = $368,663

Issue Date FY: 2016 ( Subtotal = $368,663 )
2016	2016	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/23/2015	EXTENSION WITH OR WITHOUT FUNDS	$331,796
2016	2016	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$36,867
														Subtotal = $368,663

Issue Date FY: 2015 ( Subtotal = $368,663 )
2015	2015	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/16/2014	NON-COMPETING CONTINUATION	$331,796
2015	2015	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/21/2015	NON-COMPETING CONTINUATION	$36,867
														Subtotal = $368,663

Issue Date FY: 2014 ( Subtotal = $368,663 )
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/21/2014	NON-COMPETING CONTINUATION	$36,867
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/10/2013	NON-COMPETING CONTINUATION	$331,796
														Subtotal = $368,663

Issue Date FY: 2013 ( Subtotal = $368,663 )
2013	2013	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/7/2012	NEW	$368,663
														Subtotal = $368,663

Grand Total All Awards = $6,393,560

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Intestinal CD4 T cell responses to dietary and microbial antigens

Award Number: R01DK093674

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2013

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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