# Intestinal IgA B cell receptor-specific signals integrate germinal center selection with humoral responses to commensals

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $209,375

## Abstract

Abstract
B lymphocytes in the gastrointestinal tract are constantly stimulated by microbial antigens. In order to prevent
commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response
against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep
process of B cell proliferation and selection in the germinal center, which eventually gives rise to either
antibody-secreting plasma cells or memory B cells.
Intestinal B cells are mainly expressing immunoglobulin A (IgA), but how this specific antigen receptor isotype
shapes B cell fate and antibody response in the gut is poorly understood. Moreover, dysregulation of IgA
response is associated with increased infection susceptibility and autoinflammation at the mucosal interfaces.
Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of
individual B cell clones in the gut remains a central question in immunology with clear translational
implications.
Several lines of evidence indicate that distinct B cell receptor isotypes act as intrinsic regulators of germinal
center B cell response. However, how B cells integrate IgA antigen receptor signaling with germinal center
dynamics and antibody response remains undefined to date.
In this application we test the hypothesis that surface IgA directly controls germinal center B cell response
through its enhanced intracellular signaling and Ca2+ release. This leads to the generation of a lower
threshold of B cell activation, therefore allowing B cell specific for poorly immunogenic commensal species to
be recruited into the germinal center and to participate to the humoral response. We also hypothesize that
IgA signaling prevents counterselection mediated by FAS, allowing survival of low affinity B cells.
Accumulating evidence indicates IgA coating of commensals is less dependent on antigen affinity, but the
mechanisms underpinning this phenotype have not been investigated so far.
Our aims are: 1) to dissect the role of IgA-dependent BCR signaling on cell migration into the intestinal
tissue and on the quality of the antibody response; and 2) to define the role of Fas-FasL axis in counter-
selecting mucosal IgA+ germinal center B cells for efficient intestinal response.
The proposed studies examine a very poorly understood crosstalk between IgA signaling and adaptive
immune system activation in the gut. It is our expectation that these studies will increase our understanding
of how intestinal antigen recognition shapes B cell responses and adaptive immunity both at steady state and
during enteric infections. Furthermore, our studies will provide a foundation for better understanding of the
relationship between BCR-intracellular signaling and differentiation of gut-homing B lymphocytes that assure
mucosal humoral immunity.

## Key facts

- **NIH application ID:** 10738301
- **Project number:** 5R21AI173903-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Andrea Reboldi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2022-11-09 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10738301

## Citation

> US National Institutes of Health, RePORTER application 10738301, Intestinal IgA B cell receptor-specific signals integrate germinal center selection with humoral responses to commensals (5R21AI173903-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10738301. Licensed CC0.

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