Monday, June 30, 2025 6/30/2025

NFAT, bZIP proteins, and transcriptional programs in lymphocytes

Award Number: R01AI109842
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: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2025

Group Awards By:

View Award Description

NFAT, bZIP proteins, and transcriptional programs in lymphocytes - ABSTRACT Blocking antibodies to CTLA4, PD-1, and other inhibitory surface receptors expressed on exhausted T cells, or blocking antibodies to the PD-1 ligands PD-L1 and PD-L2 expressed by tumor and stromal cells, have been remarkably successful at promoting long-term tumor regression. Combinations of blocking antibodies to multiple inhibitory receptors, often reinforced with activating antibodies to costimulatory receptors, have been more effective than treatment with individual blocking antibodies alone. Nevertheless, despite these successes, many patients still fail to respond to `immune checkpoint blockade' therapies, emphasizing the need to understand immune cell `exhaustion' at a molecular level, both in mouse models and in humans. The calcium- and calcineurin-regulated transcription factor NFAT is a driver of the transcriptional responses underlying T cell activation. The T cell activation program mainly depends on cooperative binding of NFAT and its transcriptional partner AP1 (Fos-Jun) at composite DNA sites in gene promoters and enhancers. In parallel, NFAT can activate a second transcriptional program that imposes a hyporesponsive state, typically termed `exhaustion' or `dysfunction'. This second NFAT-mediated program becomes prominent in CD8+ T cells exposed to persistent antigen stimulation during chronic viral infections and cancer, and is characterized by a spectrum of functionally compromised states with decreased cytokine expression and increased expression of multiple inhibitory receptors (PD-1, CTLA4, LAG3, TIM3, TIGIT). Thus an effective alternative to combination checkpoint blockade therapies might be to modulate the balance between the NFAT-mediated programs of activation and exhaustion, and thereby to skew tumor-infiltrating T cells away from exhaustion and towards effector function. We will test this hypothesis here. Our experiments with an engineered NFAT1, minimally modified to prevent its interaction with AP1, have established that the transcriptional program of exhaustion is independent of the NFAT1-AP1 interaction. We have identified important targets of NFAT in the exhaustion program, including transcription factors of the Nr4a and Tox families. Moreover, we have shown that Nr4a transcription factors act in exhausted tumor-infiltrating T cells, in part, by repressing the expression or activation of bZIP transcription factors that would otherwise promote an effector-like phenotype. In Aim 1, we will identify and characterize the bZIP transcription factors that are most effective in maintaining the effector function of tumor-infiltrating CD8+ T cells under conditions that would ordinarily lead to exhaustion; in Aim 2, we will define the differential roles of two NFAT family members, NFAT1 and NFAT2, in the transcriptional program of exhaustion; and in Aim 3, we will use novel proteomic strategies to identify NFAT-interacting proteins that cooperate with NFAT to impose the exhaustion program. Our proposed studies will test the hypothesis that CD8+ TILs are functionally silenced by a cell-intrinsic transcriptional program mediated by persistent NFAT signalling coupled with repression of bZIP transcription factors. The results will contribute to a broad mechanistic understanding of the transcriptional mechanisms operating in mouse and human tumor-infiltrating T cells. !


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 = $0 )
2025	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	36	5/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $842,353 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	36	2/27/2024	NON-COMPETING CONTINUATION	$758,119
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	36	5/29/2024	NON-COMPETING CONTINUATION	$84,234
														Subtotal = $842,353

Issue Date FY: 2023 ( Subtotal = $842,353 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	35	2/15/2023	NON-COMPETING CONTINUATION	$842,353
														Subtotal = $842,353

Issue Date FY: 2022 ( Subtotal = $842,353 )
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	34	2/28/2022	NON-COMPETING CONTINUATION	$842,353
														Subtotal = $842,353

Issue Date FY: 2021 ( Subtotal = $1,068,565 )
2021	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	33	2/12/2021	NON-COMPETING CONTINUATION	$842,353
2021	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	32	6/3/2021	COMPETING CONTINUATION	$226,212
														Subtotal = $1,068,565

Issue Date FY: 2020 ( Subtotal = $669,740 )
2020	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	32	3/10/2020	COMPETING CONTINUATION	$669,740
2020	2018	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	31	3/18/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $669,740

Issue Date FY: 2018 ( Subtotal = $732,684 )
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	31	7/19/2018	NON-COMPETING CONTINUATION	$732,684
														Subtotal = $732,684

Issue Date FY: 2017 ( Subtotal = $732,684 )
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	30	7/13/2017	NON-COMPETING CONTINUATION	$732,684
														Subtotal = $732,684

Issue Date FY: 2016 ( Subtotal = $732,684 )
2016	2016	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	29	7/14/2016	NON-COMPETING CONTINUATION	$732,684
														Subtotal = $732,684

Issue Date FY: 2015 ( Subtotal = $732,684 )
2015	2015	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	28	7/24/2015	NON-COMPETING CONTINUATION	$678,945
2015	2015	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	28	8/20/2015	NON-COMPETING CONTINUATION	$53,739
														Subtotal = $732,684

Issue Date FY: 2014 ( Subtotal = $678,945 )
2014	2014	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	27	7/29/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$678,945
														Subtotal = $678,945

Grand Total All Awards = $7,875,045

Top

All Categories

About

Search

Reports

Data Submission

Award Information

NFAT, bZIP proteins, and transcriptional programs in lymphocytes

Award Number: R01AI109842

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: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer