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Perforin 2 controls unconventional cytokine release from mucosal APC

Award Number: U01AI163062
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Perforin 2 controls unconventional cytokine release from mucosal APC - Perforin 2 controls unconventional cytokine release from mucosal APC Project Summary How professional antigen presenting cell (APC) populations focally deliver cytokines to T cells for shaping the pro-inflammatory vs. anti-inflammatory status of mucosal tissue remains incompletely understood. In particular, cytokines that lack N-terminal peptide sequence such as the IL-1 family cytokine IL-33 can't access conventional protein secretion pathways, which has led to the prevailing view that cell death is responsible for IL-33 release. This project is built upon an exciting set of preliminary data demonstrating that mucosal conventional dendritic cell (cDC) subsets, in both humans and mice, express the transmembrane pore-forming protein Perforin-2, which at least in mice, facilitates IL-33 secretion. While in human cDC, we find Perforin-2 expression primarily in an interferon regulatory factor 4 (IRF4) subset indicating the cDC2 lineage, in mouse cDC, we find Perforin-2 in the CD103+ cDC1 subset known to express the transcription factors Irf8 and Batf3. Irrespective of this lineage distinction, both human and mouse CD11c+ cells in the respiratory mucosa contain cytoplasmic IL-33 protein. Our data demonstrate that inhibition of Perforin-2 activity prevents IL-33 release from cDC and inhibits the proliferative expansion of a poorly understood ST2+GATA3+Foxp3+Treg subset. Given that Perforin-2 has been shown to also regulate Type 1 IFN signaling through controlling IFNAR responsiveness, we propose an important regulatory mechanism exists in humans and mice that is dependent upon mucosal APC that express Perforin-2. This project tests the central hypothesis that APC require Perforin-2 as an inducible plasma membrane conduit for unconventional cytokine delivery at the mucosal interface. Three specific aims (SA) will be investigated. SA1 will determine whether Perforin-2+ APC predict Treg subset abundance in sinonasal mucosa and define the transcriptional landscape of Perforin-2+ APC. SA2 will define the Perforin-2 domains required for IL-33 release, the diversity of Perforin-2-dependent secreted molecules, and the requisite intracellular trafficking machinery responsible for Perforin-2 plasma membrane localization during APC-T cell interactions. SA3 will directly test whether cDC1 and/or cDC2 subsets preferentially use Perforin-2 for driving pathogen-specific T cell responses in mouse models of respiratory virus or helminth infection. Taken together, this MIST project stands to uncover a new paradigm for understanding how cDC instruct immunity within the respiratory mucosa.


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 = $443,804 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	005	6	5/20/2025	NON-COMPETING CONTINUATION	$433,804
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	006	4	6/12/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	4	5/6/2025	NON-COMPETING CONTINUATION	-$80,099
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	003	4	5/6/2025	SUPPLEMENT FOR EXPANSION	-$25,070
2025	2024	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	004	5	5/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$105,169
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	4/16/2025	NON-COMPETING CONTINUATION	-$78,537
2025	2024	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	001	5	4/16/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,537
														Subtotal = $443,804

Issue Date FY: 2024 ( Subtotal = $574,356 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	4	5/23/2024	NON-COMPETING CONTINUATION	$456,163
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	4	5/24/2024	SUPPLEMENT FOR EXPANSION	$89,577
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	3/4/2024	SUPPLEMENT FOR EXPANSION	$28,616
														Subtotal = $574,356

Issue Date FY: 2023 ( Subtotal = $456,167 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	5/25/2023	NON-COMPETING CONTINUATION	$456,167
														Subtotal = $456,167

Issue Date FY: 2022 ( Subtotal = $455,000 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	5/26/2022	NON-COMPETING CONTINUATION	$455,000
														Subtotal = $455,000

Issue Date FY: 2021 ( Subtotal = $455,000 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	8/20/2021	NEW	$455,000
														Subtotal = $455,000

Grand Total All Awards = $2,384,327

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Perforin 2 controls unconventional cytokine release from mucosal APC

Award Number: U01AI163062

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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