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TGFβ Restricts Tfh2 Differentiation but Augments IgE-Mediated Mast Cell Function: Critical and Opposing Roles in Allergic Disease

Award Number: K22AI187413
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/18/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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TGFβ Restricts Tfh2 Differentiation but Augments IgE-Mediated Mast Cell Function: Critical and Opposing Roles in Allergic Disease - T follicular cells (Tfh) act as effector helper cells that are critical in B cell class switching into IgE producing plasma cells. Mast cells (MC) express the high affinity IgE receptor, FcεRI, that when complexed with IgE and antigen, lead to degranulation and the release of preformed mediators irrevocably tied to anaphylactic reactions. Learning more about Tfh and MC function and development can provide knowledge on new therapeutic targets for unmet clinical needs. TGFβ is a complex cytokine that plays a well appreciated role in the immune system, however the effects of TGFβ signaling disruption on IgE production and responses and how this may impact allergic disease is still poorly understood. Given the potent and diverse role of TGFβ, a better understanding of this pathway and its relationship to allergic disease pathogenesis is warranted. To clarity this, we study Tfh and MC function in patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in TGFBR1 and TGFBR2, who are highly predisposed to food allergy, asthma, allergic rhinitis and eczema. Using a mouse model of LDS with a knock-in allele (Tgfbr1WT/Mut ) of an LDS mutation and patient samples, we found that LDS patients and mice have decreased lymphocyte pSmad2/3 signaling downstream of TGFβ, increased Tfh2 cells, decreased Tfh17 cells, and increased food specific IgE. LDS Tfh cells displayed a reduced STAT3 and SOCS1 signaling signature. Furthermore, LDS T cells demonstrated increased PI3Kγ transcription and activity, which could be replicated with siRNA knockdown of the TGFβ dependent transcriptional repressor, SnoN, and prevented with chemical inhibition of PI3Kγ. In support, in vivo PI3Kγ blockage resulted in decreased Tfh accumulation and IgE production in response to fed OVA antigen. Furthermore, LDS mice were unexpectedly protected from IgE mediated anaphylaxis. In addition, cultured mice and human LDS MC’s displayed suppressed IgE-mediated degranulation compared to healthy controls. Mechanistically, IL-33 responses were found to be enhanced in LDS MCs, which was tied to decreased IgE mediated functions since LDS mice deficient in the IL-33 receptor displayed a partially corrected anaphylaxis phenotype. Furthermore, transcriptome analysis revealed that the neuropilin (NRP) signaling pathway was enhanced in LDS MCs. MC specific NRP1 knockout (cKO) led to enhanced IgE driven anaphylaxis, suggesting a negative regulatory role for NRP1 in MC mediated IgE functions. Therefore, this project will test the hypothesis that TGFβ signaling suppresses Tfh2 development via PI3Kγ and SOCS1-STAT3 but augments MC IgE responses by blocking the negative feedback loops via ST2/IL-33 and NPR1.


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 = $108,000 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	2	5/11/2026	NON-COMPETING CONTINUATION	$108,000
														Subtotal = $108,000

Issue Date FY: 2025 ( Subtotal = $162,000 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	1	6/18/2025	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $270,000

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TGFβ Restricts Tfh2 Differentiation but Augments IgE-Mediated Mast Cell Function: Critical and Opposing Roles in Allergic Disease

Award Number: K22AI187413

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/18/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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