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Self-Peptides Bound to MHC Class II in T Cell Selection

Award Number: R01AI034206
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: 09/01/1992
PERIOD OF PERFORMANCE END DATE: 10/31/2029

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Self-Peptides Bound to MHC Class II in T Cell Selection - Abstract Regulatory T (Treg) cells, serving as life-long guardians of the immune system, are distinguished by constitutive expression of transcription factor (TF) Foxp3, playing a critical role in their differentiation, function and fitness. Our previous studies showed that Foxp3 expression is stable in fully differentiated Treg cells, while recently generated Treg cells can lose Foxp3 expression. Furthermore, Treg cell functionality and Foxp3 expression can be compromised in severe disease settings. Although the unresolved issue of resilience vs. vulnerability of Foxp3-dependent Treg functional program is of major basic and clinical significance, presently the role for Foxp3 protein in functional and transcriptional program of differentiated Treg cells in vivo remains unknown. Our preliminary studies of induced degradation of Foxp3 protein in vivo using novel optimized Foxp3 auxin-degron model raise the possibility of a remarkable resilience of ‘mature’ Foxp3-dependent Treg cell function and gene regulatory network (GRN) in adulthood, but not of ‘immature’ ones in early life. Based on our published and preliminary studies we hypothesize that during Treg differentiation, initially vulnerable Foxp3 dependent GRN approaches a temporally self-sustained (attractor) state over a surprisingly long timescale due to a requirement for persistent Foxp3 activity for this ‘maturation’. Upon assumption of this state, its resilience ensures extended stability of Treg function even upon the loss of Foxp3 expression. In this proposal we will test this hypothesis by elucidating Foxp3 GRN underlying Treg cell function, dynamics of its establishment and its resilience to Foxp3 loss in physiologic and inflammatory settings using genetic gain- and loss-of-function approaches. The following Specific Aims will be pursued: 1) elucidate a role of Foxp3 in the functional program of Treg cells and its resilience in early life and adulthood under physiologic conditions and upon inflammatory challenges; 2) investigate dynamic of Foxp3-dependent regulation of gene expression and chromatin in Treg cells using chemogenetic gain- and loss-of-function approaches; 3) elucidate mechanisms of resilience of Foxp3-dependent gene expression and functional programs using CRISPR and CRISPRi/a Perturb-seq approaches. These studies will provide mechanistic, gene-regulation level framework for understanding of Treg cell differentiation and function in health and disease and inform novel approaches for therapeutic targeting of Treg cells and development of adoptive Treg cell therapies for autoimmune and inflammatory disorders.


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 = $677,758 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	31	12/5/2024	COMPETING CONTINUATION	$0
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	31	11/18/2024	COMPETING CONTINUATION	$677,758
2025	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	30	2/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $677,758

Issue Date FY: 2023 ( Subtotal = $595,054 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	30	8/11/2023	NON-COMPETING CONTINUATION	$595,054
														Subtotal = $595,054

Issue Date FY: 2022 ( Subtotal = $595,054 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	29	8/15/2022	NON-COMPETING CONTINUATION	$595,054
														Subtotal = $595,054

Issue Date FY: 2021 ( Subtotal = $595,054 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	28	8/11/2021	NON-COMPETING CONTINUATION	$595,054
														Subtotal = $595,054

Issue Date FY: 2020 ( Subtotal = $595,054 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	27	8/6/2020	NON-COMPETING CONTINUATION	$595,054
														Subtotal = $595,054

Issue Date FY: 2019 ( Subtotal = $595,054 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	26	9/19/2019	COMPETING CONTINUATION	$595,054
														Subtotal = $595,054

Issue Date FY: 2007 ( Subtotal = $318,698 )
2007	2007	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	15	1/12/2007	NON-COMPETING CONTINUATION	$318,698
														Subtotal = $318,698

Issue Date FY: 2006 ( Subtotal = $328,358 )
2006	2006	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	14	12/15/2005	NON-COMPETING CONTINUATION	$328,358
														Subtotal = $328,358

Issue Date FY: 2005 ( Subtotal = $336,401 )
2005	2005	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	13	12/22/2004	NON-COMPETING CONTINUATION	$336,401
														Subtotal = $336,401

Issue Date FY: 2004 ( Subtotal = $336,538 )
2004	2004	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	12	12/25/2003	NON-COMPETING CONTINUATION	$336,538
														Subtotal = $336,538

Issue Date FY: 2003 ( Subtotal = $150,493 )
2003	2003	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98195	KING	USA	Indicates awards funded from multiple programs	000	11	6/16/2003	COMPETING CONTINUATION	$150,493
														Subtotal = $150,493

Issue Date FY: 2002 ( Subtotal = $211,683 )
2002	2002	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	10	7/1/2002	NON-COMPETING CONTINUATION	$211,683
														Subtotal = $211,683

Issue Date FY: 2001 ( Subtotal = $205,519 )
2001	2001	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98195	KING	USA	Allergy and Infectious Diseases Research	000	9	7/16/2001	NON-COMPETING CONTINUATION	$205,519
														Subtotal = $205,519

Issue Date FY: 2000 ( Subtotal = $199,532 )
2000	2000	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	8	6/7/2000	NON-COMPETING CONTINUATION	$199,532
														Subtotal = $199,532

Issue Date FY: 1999 ( Subtotal = $193,720 )
1999	1999	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	7	6/29/1999	NON-COMPETING CONTINUATION	$193,720
														Subtotal = $193,720

Issue Date FY: 1998 ( Subtotal = $186,881 )
1998	1998	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	6/11/1998	COMPETING CONTINUATION	$186,881
														Subtotal = $186,881

Grand Total All Awards = $6,120,851

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Self-Peptides Bound to MHC Class II in T Cell Selection

Award Number: R01AI034206

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: 09/01/1992

PERIOD OF PERFORMANCE END DATE: 10/31/2029

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