Molecular mechanisms linking antigen format and affinity to distinct B cell responses

Active Project Grant Awarded Last action

Award ID
F32AI200252
Recipient
Awarding agency
Obligated
$76,780

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Place of performance
San Francisco, CA 94143, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Quick answers

Who received award F32AI200252?

F32AI200252 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 28, 2026.

How much is award F32AI200252 worth?

$76,780 has been obligated on F32AI200252.

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