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TCR signaling control of thymic Treg selection and immune homeostasis

Award Number: R01AI143976
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: 12/04/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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TCR signaling control of thymic Treg selection and immune homeostasis - Abstract Neonatal thymic-derived Foxp3+ T regulatory cells (tTregs) are required for the development of immune homeostasis and limiting organ specific autoimmune disease. The molecular details of TCR-pMHC interactions, and the specific downstream signaling pathways that allow neonatal tTregs to develop, seed peripheral tissues and regulate acute inflammation are not well understood. We hypothesize that a subset of neonatal tTregs distinguishes health from disease via the expression of TCR with specificity for self-ligands that are upregulated during inflammatory conditions. This tTreg TCR recognition property manifests as graded levels of immune suppression based on the context and magnitude of the inflammatory setting. Preliminary data further suggest that the development of these tTreg clones within the neonatal selection window is temporally constrained by negative selection, and is predicated on kinetic proofreading, with TCR-self-pMHC dwell times within a conventional binding mode as a key to specifying tTreg development. To test our hypothesis, we will first identify endogenous self-ligands recognized by Foxp3+ CD4 tTreg cell subsets. Our approach is based on our proven ability to identify self-ligands recognized by T cells, paired with mass spectrometry of MHC-II bound self-peptides presented on APC isolated from different anatomical locations, as well as high-throughput pipelines for determining recognition properties of individual T cell clonotypes. Using paired sets of TCR-self-pMHC combinations our second aim will directly examine whether neonatal tTreg selection is based the dwell time of the interaction, and assess the influence of “unconventional” TCR/self- pMHC binding modes in selecting the neonatal tTreg repertoire. Aim 3 will identify synergies between self- pMHC presentation by thymic APCs and the quality of TCR signals generated by thymocytes that define the neonatal tTreg selection window. Signaling by the Tec family kinase, Itk, is proposed to regulate a signaling threshold that separates Foxp3 Treg selection from late stage deletion by amplifying pro-survival TCR signals derived from moderate dwell-time ligands via NFAT and NF-κB signaling pathways. Finally, in mature tTregs, we propose that Itk functions to amplify weak TCR responses, thereby allowing mature Tregs to recognize gradients in self-antigen displayed. These studies will provide important insights into the fine-tuning of T cell responses and the signaling pathways that discriminate effector cells from regulatory cells, leading to rational approaches in the design of therapeutics to manipulate immune responses for treatments of cancer and autoimmune diseases.


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 = $575,269 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	5	11/16/2023	NON-COMPETING CONTINUATION	$517,743
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	5	5/16/2024	NON-COMPETING CONTINUATION	$57,526
														Subtotal = $575,269

Issue Date FY: 2023 ( Subtotal = $577,145 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	11/8/2022	NON-COMPETING CONTINUATION	$577,145
														Subtotal = $577,145

Issue Date FY: 2022 ( Subtotal = $578,865 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	11/23/2021	NON-COMPETING CONTINUATION	$578,865
														Subtotal = $578,865

Issue Date FY: 2021 ( Subtotal = $580,443 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	11/24/2020	NON-COMPETING CONTINUATION	$580,443
														Subtotal = $580,443

Issue Date FY: 2020 ( Subtotal = $598,876 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	12/4/2019	NEW	$598,876
														Subtotal = $598,876

Grand Total All Awards = $2,910,598

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TCR signaling control of thymic Treg selection and immune homeostasis

Award Number: R01AI143976

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: 12/04/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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