# Mechanism of MHC heterozygote advantage during anti-commensal germinal center B cell selection

> **NIH NIH R21** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $186,250

## Abstract

Project Summary
Heterozygosity at classical major histocompatibility complex (MHC) genes is thought to benefit host fitness by
increasing the breadth of antigens that can be targeted by mature effector T and B cell lymphocyte
populations. A large number of studies support the first prediction by demonstrating that MHC heterozygosity is
associated with enhanced resistance to infection. However, currently there is no data on the second major
prediction of this hypothesis that pertains to the underlying mechanism thought to drive this fitness benefit. In
this proposal, we focus specifically on defining the role of MHC heterozygosity on germinal center (GC)
dynamics within Peyer’s patches (PPs) of the gut. GCs are micro-environments with PPs where unique B cell
clones are selected to become plasma cells that will ultimately migrate to the gut lamina propria and secrete
high affinity IgA antibodies. Here, we provide data indicating that MHC heterozygosity is associated with the
development of fewer GC B cells in PPs. Also, despite having the same number of CD4+ follicular Helper T
(TFH) cells, there is a weaker relationship between GC B cell and TFH cell abundance, which implies weaker
cognate T:B cell interactions in the PP GCs of MHC heterozygote mice. Surprisingly, this is correlated with
enhanced binding of commensal microbes with high affinity IgA, but not higher IgA secretion into the gut.
Together, these observations support the hypothesis that weaker GC responses in MHC heterozygotes results
in greater binding of commensal microbes with high affinity IgA. Based on this hypothesis, we make the
following two predictions; (1) that MHC heterozygosity reduces inter-clonal competition among B cell clones
during GC reactions in PPs, and (2) that this results in the generation of a diverse IgA-secreting plasma cell
repertoire that binds a wider array of commensal microbes with IgA. The intent of this
Developmental/Exploratory (R21) research proposal is to explicitly test these two predictions using innovative
approaches. Innovation includes the use of two novel MHC congenic mouse models that will allow us to
directly measure the cell-intrinsic effect of MHC heterozygosity on B cell competition in GCs, and to visually
demonstrate a diversifying effect of MHC heterozygosity on GC clonal diversity in vivo. The objective of
Specific Aim #1 will be to test the prediction that B-cell-intrinsic MHC heterozygosity reduces the competitive
ability of B cells during GC reactions in gut PPs. B cells from MHC homozygote and MHC heterozygote mice
will be adoptively transferred in equal ratios into B-cell-deficient MHC-matched transfer recipients and their
relative representation in the germinal center B cell pool will be enumerated using donor-specific allotypic
markers (CD45.1/CD45.2). A second model using multi-fluorescent lineage-tracking (“Brainbow2.0” a.k.a.
“Confetti”) mice will be utilized to visually quantify differences in GC clonal diversity among MHC hom...

## Key facts

- **NIH application ID:** 9934111
- **Project number:** 5R21AI142409-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Jason L Kubinak
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934111

## Citation

> US National Institutes of Health, RePORTER application 9934111, Mechanism of MHC heterozygote advantage during anti-commensal germinal center B cell selection (5R21AI142409-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934111. Licensed CC0.

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