# Progenitors, Mechanisms of Differentiation, and Functions of Lung M Cells

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $795,168

## Abstract

M cells have been shown to sample luminal antigens and use transcytosis to deliver these antigens to underlying
antigen presenting dendritic cells. Thus, they serve as key regulators of mucosal immunity. Despite the vast body of
literature on the immunologic role of M cells in other mucosal organs, airway M cells have only recently been described
and almost no functional or molecular characterization has been performed. We present the first single cell transcriptomes
of murine airway M cells and identify airway M cell signaling cascades that regulate inflammation. We have discovered
that airway M cells occur as solitary cells in the murine trachea and as patches in the murine small airway, and we report
the directed differentiation of human airway M cells from primary human airway epithelium. Finally, we demonstrate that
airway M cells are induced by the administration of the signaling factor RANKL, treatment with Lipopolysaccharide (LPS),
and influenza infection. Interestingly, M cells can occur as solitary cells, but in the setting of physiologic stimuli like LPS
or influenza infection, patches of M cells are associated with lymphoid follicles suggesting a functional epithelial-immune
unit.
 In this grant application, we propose to use our combined expertise in stem cell biology, epithelial biology, lung
inflammation, and influenza infection to define the functional biology of lung M cells. We will start by defining the cellular
origins of murine and human airway M cells. We have now generated a comprehensive battery of murine genetic driver
lines for lineage tracing all the cells of airway epithelium. Herein, we propose to deploy this set of murine lines, for the first
time, in order to precisely define all the putative parental epithelial cell types that can give rise to M cells. We will also
clarify the role of RANKL-RANK signaling pathways in murine models of inflammation. Finally, to define airway M cell
functions, we constructed a new Sox8-CreER driver mouse that allows us to specifically label, genetically modify, and
ablate M cells. We will integrate these genetic reagents with existing murine disease models to elucidate the role of
functional roles of M cells in models of airway inflammation and influenza infection. Lastly, we will dissect the molecular
mechanisms of two candidate chemokines that govern M cell-immune cell interactions using genetic and pharmacological
manipulation in combination with a novel tracheal explant and lung slice live imaging platform.

## Key facts

- **NIH application ID:** 10502088
- **Project number:** 1R01HL164563-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JAYARAJ RAJAGOPAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $795,168
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10502088

## Citation

> US National Institutes of Health, RePORTER application 10502088, Progenitors, Mechanisms of Differentiation, and Functions of Lung M Cells (1R01HL164563-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10502088. Licensed CC0.

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