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DECODING THE INTERACTIONS BETWEEN T CELL RECEPTORS AND PEPTIDE-MHC

Award Number: R01AI136514
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: 06/20/2018
PERIOD OF PERFORMANCE END DATE: 09/21/2025

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DECODING THE INTERACTIONS BETWEEN T CELL RECEPTORS AND PEPTIDE-MHC - Summary Conventional ɑβ T cell receptor (TCR) recognition of a cognate peptide-Major Histocompatibility Complex (pMHC) is central to adaptive immune recognition of pathogens and pathologically associated self-proteins. Despite substantial progress in structural prediction of protein-protein interactions with tools such as AlphaFold and RoseTTAFold, de novo prediction of TCR specificity (target pMHC) from TCR sequence has not yet been realized. Indeed, within the largest databases of curated TCR specificities, only ~105 unique TCR:pMHC assignments have been curated, and these are focused on <100 unique pMHC epitopes. In our previous work, we established that >200 unique receptors recognizing the same epitope are required to confidently predict whether a previously unobserved receptor belongs to the same specificity group. This work demonstrates that once data are sufficiently dense, local prediction of specificity becomes feasible. It follows that the current sparse nature of the available data is the major restriction to advancing the field. Thus, our central hypothesis is that advancing predictive models for TCR specificity requires a dramatic increase in the magnitude and diversity of curated TCR-pMHC data, which in turn requires new approaches for generating such useful data sets. In three Aims, we will address major limitations of the current epitope discovery and TCR characterization pipelines. In Aim 1, we will improve methods for relating single chain TCR sequences to specific peptides for generating large libraries of well-curated TCRα or TCRβ associations with individual epitopes. In addition to supporting our central goal, these data will have significant independent utility for immune profiling and diagnostics. In Aim 2, we will establish methods for assigning paired chain TCRɑβ data from single cell experiments to epitope pools, extending our recently reported reverse epitope discovery pipeline. Aim 3 will integrate public data and the data generated in Aims 1 and 2, with novel structural and computational approaches to generate improved de novo specificity prediction algorithms. These Aims will be accomplished by accessing our collection of longitudinally sampled PBMCs from >4000 humans across well-curated cohorts from diverse ancestries and infection histories.


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: 2026 ( Subtotal = $0 )
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	8	2/2/2026	NON-COMPETING CONTINUATION	-$799,765
2026	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	9	1/30/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$799,765
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $864,012 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	8	6/12/2025	NON-COMPETING CONTINUATION	$864,012
2025	2022	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	12/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $864,012

Issue Date FY: 2024 ( Subtotal = $867,150 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	7	5/17/2024	NON-COMPETING CONTINUATION	$867,150
														Subtotal = $867,150

Issue Date FY: 2023 ( Subtotal = $890,694 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	6	3/10/2023	COMPETING CONTINUATION	$890,694
														Subtotal = $890,694

Issue Date FY: 2022 ( Subtotal = $681,906 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	5/20/2022	NON-COMPETING CONTINUATION	$681,906
														Subtotal = $681,906

Issue Date FY: 2021 ( Subtotal = $681,906 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	4	5/17/2021	NON-COMPETING CONTINUATION	$681,906
														Subtotal = $681,906

Issue Date FY: 2020 ( Subtotal = $681,906 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	3	5/2/2020	NON-COMPETING CONTINUATION	$681,906
2020	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	2/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $681,906

Issue Date FY: 2019 ( Subtotal = $681,906 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	5/14/2019	NON-COMPETING CONTINUATION	$681,906
														Subtotal = $681,906

Issue Date FY: 2018 ( Subtotal = $721,656 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	1	6/20/2018	NEW	$721,656
														Subtotal = $721,656

Grand Total All Awards = $6,071,136

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DECODING THE INTERACTIONS BETWEEN T CELL RECEPTORS AND PEPTIDE-MHC

Award Number: R01AI136514

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: 06/20/2018

PERIOD OF PERFORMANCE END DATE: 09/21/2025

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