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Mechanobiology of the immune synapse: signal integration via actin dynamics

Award Number: R01AI147118
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: 11/24/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Mechanobiology of the immune synapse: signal integration via actin dynamics - ABSTRACT Mechanical force is essential for T cell activation. It activates TCR signaling, and allows the T cell to sample the quality of TCR-pMHC interactions. This greatly expands the dynamic range of TCR responses and permits antigen discrimination during thymic selection, T cell priming, and effector responses. Our understanding of how force influences TCR-pMHC interactions has advanced significantly, thanks to biophysical studies at the single molecule level. However, there are large gaps in knowledge at the cell biological level. This project seeks to identify the biochemical and mechanical circuits within the TCR signal transduction network that permit the rapid translation of small differences in the physical characteristics of the TCR–pMHC interactions into distinct cellular responses. During the first project period, we showed that the T cell actin network exerts force on the integrin LFA-1 as well as the TCR, supporting mechanical crosstalk that influences the activation of both molecules. Interestingly, this process is sensitive to the biophysical features of the stimulatory surface, including ligand mobility and stiffness. These parameters are physiologically relevant, as they are regulated during DC maturation to optimize T cell priming. Further analysis reveals that this mechanobiology also impacts cytoplasmic signaling molecules that interact with the actin cytoskeleton. In particular, we find that T cell stiffness responses involve phosphorylation of the stretch-sensitive adapter protein CasL. On the basis of these findings, we hypothesize that TCR-induced actin polymerization allows the cell to sense biophysical cues provided by the interacting APC, initiating mechanical feedback loops that modulate force-dependent signaling of cell surface receptors and intracellular signaling molecules that interact with the actin cytoskeleton. To test this hypothesis, we will carry out 3 specific aims. First, we will determine how ligand mobility influences actin dynamics and TCR signaling. Using stimulatory glass coverslips, planar bilayers with different mobility properties, and mixed mobility patterned surfaces, we will ask how the agonist strength and mobility of pMHC complexes and integrin ligands influences actin dynamics and TCR signaling. As part of this analysis, we will use TCR tension probes to define how altering the mobility of TCR and integrin ligands influences the forces experienced by the TCR. Next, we will carry out similar studies to understand how substrate stiffness influences T cell activation. We will stimulate T cells on hydrogels of varying stiffness, and analyze the effects on actin dynamics, TCR tension, and TCR signaling events needed for full T cell activation. Finally, we will investigate the role of CasL, a prototypic force-sensitive signaling intermediate. Using T cells lacking CasL, we will study the function of CasL during T cell responses to changes in ligand mobility and substrate stiffness. In addition, we will probe the signaling pathways leading to CasL phosphorylation during stiffness responses, and use mass spectrometry to identify relevant binding partners.


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 = $413,263 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	9	9/9/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	9	11/1/2024	NON-COMPETING CONTINUATION	$413,263
														Subtotal = $413,263

Issue Date FY: 2024 ( Subtotal = $426,045 )
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	8	10/30/2023	NON-COMPETING CONTINUATION	$383,441
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	8	5/15/2024	NON-COMPETING CONTINUATION	$42,604
														Subtotal = $426,045

Issue Date FY: 2023 ( Subtotal = $426,045 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	7	10/21/2022	NON-COMPETING CONTINUATION	$426,045
														Subtotal = $426,045

Issue Date FY: 2022 ( Subtotal = $426,045 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	6	10/22/2021	NON-COMPETING CONTINUATION	$426,045
														Subtotal = $426,045

Issue Date FY: 2021 ( Subtotal = $422,337 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	11/24/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$422,337
														Subtotal = $422,337

Grand Total All Awards = $2,113,735

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Mechanobiology of the immune synapse: signal integration via actin dynamics

Award Number: R01AI147118

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: 11/24/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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