# B-cell-intrinsic MHCII Signaling is a Diversifying Force of Selection on IgA Repertoires and the Gut Microbiota

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $453,793

## Abstract

Project Summary
T-cell-dependent (TD) immunoglobulin A (IgA) responses regulate the composition of the gut microbiota. How
B-cell-intrinsic MHCII signaling, which is central to the development of TD IgA responses, influences host-
microbiota interactions is unknown. MHCII is widely assumed to promote clonal diversity in effector lymphocyte
populations, but this has not been tested. Here, we present evidence in support of the argument that B cell-
intrinsic MHCII signaling controls GC dynamics, IgA repertoire diversity, and microbiota composition.
Additionally, evidence from our experiments also indicate that both B-cell-intrinsic ablation of MHCII and specific
MHC genotypes are associated with enhanced bacterial dissemination from the gut. Based on these
observations and previous work by Dr. Kubinak, this R01 seeks to address the hypothesis that B-cell-intrinsic
MHCII signaling is a diversifying force of selection promoting clonal diversity in IgA plasma cell pools
and individuality in microbiota composition. The objective of Specific Aim #1 is to define the B-cell-intrinsic
role of MHCII during GC reactions in the gut; specifically focusing on its role in shaping plasma cell repertoire
diversity. A 'Confetti' mouse model will be used to visually demonstrate the effect of MHCII ablation on GC B cell
clonal diversity in the gut. IgH sequencing will be used to determine the effect of MHCII polymorphisms and MHC
heterozygosity on IgA repertoire diversity in the gut. scRNA sequencing will be used to determine how MHCII
influences overlap in clonal diversity between mucosal and systemic plasma cell pools. RAG1-/- bone marrow
(BM) chimeras will be used to quantify the effect of MHCII on cross-seeding of gut-derived plasma cells into the
BM. Reciprocal BM chimeras will be used to determine the necessity/sufficiency of defects in B-cell-intrinsic
MHCII in regulating bacterial dissemination from the gut. The objective of Specific Aim #2 is to test that microbiota
composition is an MHCII-dependent phenotype. RAG1-/- and RAG1-/-IL7R-/- BM chimeras will be used to
determine the role gut peyer's patches play in driving MHCII-mediated IgA selection in the gut. Microbial
colonization experiments in germfree GF RAG1-/- BM chimeras will determine the effect of B-cell-intrinsic MHCII
on IgA-targeting of commensal bacteria. A RAG1-/- adoptive transfer model will be used to determine if MHCII
surface density influences IgA-mediated targeting of commensals and microbiota composition. Finally, a novel
germfree MHC congenic model will be used to explicitly define the role IgA plays in driving individuality in
microbiota composition. Results from these studies will address the B-cell-intrinsic role of MHCII in regulating
mucosal IgA responses, microbiota composition, and host health. This is a critical gap in our knowledge that is
highly relevant to human health. IgA deficiency is the most common form of antibody-deficiency in humans, is
strongly linked to genetic varia...

## Key facts

- **NIH application ID:** 10409841
- **Project number:** 5R01AI155887-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Jason L Kubinak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,793
- **Award type:** 5
- **Project period:** 2021-05-25 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409841

## Citation

> US National Institutes of Health, RePORTER application 10409841, B-cell-intrinsic MHCII Signaling is a Diversifying Force of Selection on IgA Repertoires and the Gut Microbiota (5R01AI155887-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10409841. Licensed CC0.

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