# Deciphering the immunoregulatory network governing antigen presenting myeloid cells

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2022 · $387,500

## Abstract

SUMMARY
Dendritic cells (DC) are responsible for directing T cell responses and macrophages important for modulating
tissue inflammation. A hallmark of these immune cells is their inherent plasticity to govern immunity vs. tolerance.
However, much remains unknown regarding the complex molecular networks that collectively govern
hematopoiesis, inflammation and antigen presentation. Incomplete understanding presents major obstacles to
delineating their underlying roles in health and disease, which has also hindered success in developing effective
immunotherapies. The long-term goal of the proposed research is to determine how pivotal immunoregulatory
proteins govern DC and macrophage differentiation and immune responses. Published findings by my laboratory
have begun to mechanistically define the functional roles of several important genes uniquely expressed in these
myeloid cells. These genes, which include Allograft Inflammatory Factor-1 (AIF1) and Phosphodiesterase 1b
(Pde1b), among others, were identified using a combination of high throughput transcriptomic profiling coupled
with rigorous RNAi functional screening. My laboratory demonstrated that AIF1 is selectively expressed in
conventional type 1 DC (cDC1), monocyte-derived DC (MoDC) and macrophages and serves as a scaffold to
recruit protein kinase C (PKC) in a calcium-responsive manner to promote inflammation and type 1 polarized
immune responses. Furthermore, AIF1 expression was required for successful generation of cDC1 from
hematopoietic progenitors and both MoDC and macrophages from monocyte precursors. In the context of
disease, AIF1 expression in DC and macrophages is required for initiating and sustaining insulitis and in
regulating effector responses to intracellular pathogens. In another line of studies, the phosphodiesterase protein
Pde1b was found to depress protein kinase A (PKA) activity in a calcium-dependent manner by regulating
cyclonucleotide levels in cDC1, MoDC and macrophages to promote immune effector responses. Thus, my
research group has begun to unravel how Pde1b works in concert with AIF1 to govern immunity by balancing
PKC vs. PKA activities. As important as these initial findings are, there remains several gaps in understanding
the molecular mechanics of how these genes govern immunobiology. As such, our research builds on prior
studies by now employing conditional and global knockout mice and use of innovative experimental tools to
rigorously study mechanistic roles in vivo. My laboratory will pursue the following major goals over the next five
years: (1) delineate how AIF1 and Pde1B govern differentiation of DC and macrophages in vivo; (2) describe the
intracellular processes by which other key novel immunoregulatory genes orchestrate immune responses; (3)
determine the contributing role of AIF1 in initiating inflammation and sustaining autoreactive T cell responses;
and (4) identify how intracellular pathogens antagonize AIF1 and Pde1b through disruption of ca...

## Key facts

- **NIH application ID:** 10405313
- **Project number:** 1R35GM145290-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Michael W Lipscomb
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,500
- **Award type:** 1
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405313

## Citation

> US National Institutes of Health, RePORTER application 10405313, Deciphering the immunoregulatory network governing antigen presenting myeloid cells (1R35GM145290-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405313. Licensed CC0.

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