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Molecular Mechanisms Linking Antigen Format and Affinity to Distinct B Cell Responses

Award Number: F32AI200252
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/28/2026
PERIOD OF PERFORMANCE END DATE: 11/27/2027

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Molecular Mechanisms Linking Antigen Format and Affinity to Distinct B Cell Responses - PROJECT SUMMARY. Self-reactive B cells are a normal part of the mature B cell repertoire in humans and in mice. This autoreactive subpopulation of B cells is theorized to play an important role in responding to self-like antigens (Ag) on pathogens, such as viruses, that face selection pressure to mimic host Ag in order to evade immunity. Consequently, B cells require precise mechanisms to distinguish self and foreign Ag to suppress autoimmune responses to self Ag while engaging immunogenic responses to foreign Ag. However, B cell Ag receptors (BCRs) are not simply binary sensors that recognize and make an invariant response to their cognate Ag. Instead, they are sensitive to a range of Ag affinities and can dynamically reorganize on the surface of B cells to interact with Ag in different “formats” of encounter: in solution (soluble), on virus-like particles (particulate) and on the surface of cells (membrane). In fact, Ag presented in these distinct formats – and across a range of affinities – elicit strikingly different B cell responses. Stereotypically, soluble Ag trigger tolerogenic responses by B cells, while particulate and membrane Ag can each induce distinct immunogenic responses. However, the molecular mechanisms that integrate Ag format and affinity to control B cell signaling and fate remain incompletely understood. Long-term, we aim to exploit new molecular insights gained from this work to enhance anti-tumor and anti-pathogen B cell responses and to restore tolerance in autoimmunity. In this proposal, we leverage a unique platform that produces model Ag – with variants spanning five orders of magnitude of Ag:BCR affinity – in three physiologically relevant formats: soluble, particulate (Ag-decorated virus-sized exosomes) and membrane (Ag presented on cell surfaces). We propose to: (1) Identify proximal biochemical pathways that integrate Ag format and affinity to toggle between tolerogenic and immunogenic responses. We will use transgenic mouse models to dissect the roles of CD19, CD22 and the Src family tyrosine kinase Lyn in modulating B cell responses to distinct Ag formats and affinities. We will also edit B cells ex vivo to identify candidate substrates of Lyn that suppress B cell responses to soluble Ag and integrate affinity information to tune signaling outcomes. (2) Elucidate tolerogenic and immunogenic transcriptional programming and B cell fate decisions elicited by distinct Ag formats and affinities. We will utilize flow-based nuclear staining approaches to quantify transcription factor nuclear translocation at single-cell resolution in B cells stimulated with soluble, particulate and membrane Ag at a range of affinities. We will exploit RNA sequencing to uncover the transcriptional programs triggered in B cells responding to different Ag formats and affinities. Lastly, we will evaluate the impact of Ag format and affinity on B cell Ag-presentation to T cells, and dependence on T cell help.


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 = $76,780 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	5/28/2026	NEW	$76,780
														Subtotal = $76,780

Grand Total All Awards = $76,780

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Molecular Mechanisms Linking Antigen Format and Affinity to Distinct B Cell Responses

Award Number: F32AI200252

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/28/2026

PERIOD OF PERFORMANCE END DATE: 11/27/2027

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