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Structural correlates of T cell receptor signaling

Award Number: R01AI103867
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: 12/01/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Structural correlates of T cell receptor signaling - Abstract: The T cell receptor interaction with peptide-MHC is unique in that each receptor has the capacity to engage and differentially respond to functionally distinct ligands. Understanding the molecular basis for these properties is important not only for mechanistic insight but for clinical translation to antigen-specific immunotherapies. In this proposal we focus on the chemistry of the TCR/pMHC interface, its role in the specificity of both the recognition and triggering phases of TCR signal initiation, and the use of this information to advance immunotherapeutic strategies. In the prior term of this proposal, we developed a technology, yeast peptide-MHC display, which enabled us obtain a deep understanding of the extent of TCR specificity and cross-reactivity. We found that TCRs are highly specific for their cognate antigens despite exhibiting cross-reactivity. This property enabled us to recover the known peptide ligands of TCRs through un-biased screening of pMHC libraries. Now, in Aim #1, this finding has opened up many exciting possibilities: principally to use pMHC display technology to query the specificity of TCRs, and to identify peptide ligands for ‘orphan’ TCRs in the natural immune system (e.g. Treg) or from pathogenic systems (e.g. cancer, autoimmunity, infectious disease). In Aim #2 we wish to then then generate high-affinity “TCR mimic” antibodies, using a novel platform approach, that specifically recognize these newly discovered ligands and enables us to track tissue expression and inducing selective killing of cells expressing these antigens. In Aim #3, we show that pMHC library technology is also powerful for understanding the relationship between TCR recognition of pMHC and signaling through the capacity of this approach to generate large panels of peptides that can be characterized with respect to signaling and structure. Using this technology, we made the surprising finding that high-affinity, but non-stimulatory pMHC ligands exist in the natural human immune repertoire. We were able to ‘isolate’ the mechanism of TCR triggering to the formation of “catch bonds” in the TCR/pMHC interface, which can decouple TCR/pMHC binding strength from signaling. In Aim #3 of the current proposal we wish to expand on our studies of non-stimulatory TCRs to better understand the molecular mechanisms of triggering at the TCR/pMHC interface, and test a new idea, ‘catch bond engineering,’ for modifying TCRs to exhibit improved target killing potency in a way that bypasses the dangers of affinity-matured TCRs in adoptive cell therapy. Collectively, this proposal aims to exploit ‘first principles’ of TCR/pMHC binding chemistry along three different fronts that have direct translational impact.


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 = $505,955 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	10	5/16/2024	NON-COMPETING CONTINUATION	$50,596
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	10	11/15/2023	NON-COMPETING CONTINUATION	$455,359
														Subtotal = $505,955

Issue Date FY: 2023 ( Subtotal = $505,955 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	9	11/10/2022	NON-COMPETING CONTINUATION	$505,955
														Subtotal = $505,955

Issue Date FY: 2022 ( Subtotal = $505,994 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	8	11/23/2021	NON-COMPETING CONTINUATION	$505,955
2022	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	5	9/23/2022	NON-COMPETING CONTINUATION	$39
														Subtotal = $505,994

Issue Date FY: 2021 ( Subtotal = $505,955 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	7	11/25/2020	NON-COMPETING CONTINUATION	$505,955
														Subtotal = $505,955

Issue Date FY: 2020 ( Subtotal = $505,955 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	002	6	4/21/2020	COMPETING CONTINUATION	$40
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	6	12/9/2019	COMPETING CONTINUATION	$505,955
2020	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	5	4/21/2020	NON-COMPETING CONTINUATION	-$40
														Subtotal = $505,955

Issue Date FY: 2018 ( Subtotal = $439,724 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	5	11/28/2017	NON-COMPETING CONTINUATION	$439,724
														Subtotal = $439,724

Issue Date FY: 2017 ( Subtotal = $443,853 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	4	12/1/2016	NON-COMPETING CONTINUATION	$443,853
														Subtotal = $443,853

Issue Date FY: 2016 ( Subtotal = $447,860 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	3	11/19/2015	NON-COMPETING CONTINUATION	$447,860
														Subtotal = $447,860

Issue Date FY: 2015 ( Subtotal = $451,752 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	2	11/18/2014	NON-COMPETING CONTINUATION	$451,752
														Subtotal = $451,752

Issue Date FY: 2014 ( Subtotal = $470,654 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	002	1	3/17/2014	NEW	$46,088
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	1	11/19/2013	NEW	$418,939
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	1	11/22/2013	NEW	$5,627
														Subtotal = $470,654

Grand Total All Awards = $4,783,657

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Structural correlates of T cell receptor signaling

Award Number: R01AI103867

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: 12/01/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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