# The role of IL-27/Lag3 axis in regulating Foxp3+ regulatory T cell function

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $469,818

## Abstract

Abstract
Immune coreceptors play an important role in tuning adaptive T cell responses. Inhibitory receptors have
emerged as a target for immune therapy because of their ability to dampen protective immunity in cancers,
chronic inflammation, or chronic viral infection. Lymphocyte activation gene-3 (Lag3) is a CD4-like surface co-
receptor expressed on the surface of activated lymphocytes. MHCII molecule is the most well characterized
Lag3 binding ligand. Lag3-MHCII binding during CD4 T-APC interaction has been shown to inhibit optimal T cell
activation. Blocking the interaction with anti-Lag3 antibody or loss-of-function mutant Lag3 renders the T cells to
hyper-proliferate and to produce more IL-2. Lag3 has thus emerged as an important immune checkpoint
molecule and a potential therapeutic target to reinvigorate anti-tumor immunity. Besides conventional T cells,
Foxp3+ regulatory T cells (Tregs), a central regulator of immunity and tolerance, are also known to express high
level of Lag3. Many studies demonstrated that Lag3 expression on Tregs is necessary for optimal Treg
suppressive function, although there has been a controversial finding that Lag3 instead limits adequate Treg
function to control autoimmune diabetes. The precise cellular and molecular mechanisms by which Lag3 controls
Treg functions remain largely unknown. During the previous funding period, we uncovered that IL-27 signaling
in Tregs is critical for Treg functions to suppress chronic inflammation. We also found that IL-27 induces Lag3
expression in Tregs. By transferring Tregs deficient in Lag3 function, we demonstrated that Lag3 is necessary
for Tregs to mitigate chronic autoimmune and allergic inflammation. The overarching goal of this renewal
application is to investigate the mechanisms by which Lag3 controls Treg function. We generated novel mouse
models in which Lag3 extracellular Ig domain necessary for the function, Lag3 cytoplasmic domain, or Lag3
KIEELE motif is selectively deleted in Tregs and found that the loss-of-function mutation or loss-of-intracellular
signal in Tregs drastically impairs Tregs’ ability to suppress autoimmune neuroinflammation. The central
hypothesis is that Tregs control inflammatory responses via the Lag3-induced intracellular pathways and that
Lag3 regulates Treg metabolic activity. Two specific aims are proposed. Specific Aim 1 will investigate the role
of Lag3 in Treg function to control autoimmune inflammation. Specific Aim 2 will investigate the molecular
mechanisms by which Lag3 regulates Treg metabolism and functions. Successful completion of the study will
not only broaden our understanding Lag3 biology but also identify novel therapeutic strategies targeting Lag3
and its downstream signaling pathways.

## Key facts

- **NIH application ID:** 10797288
- **Project number:** 2R01AI125247-07A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Booki Min
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,818
- **Award type:** 2
- **Project period:** 2017-03-15 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797288

## Citation

> US National Institutes of Health, RePORTER application 10797288, The role of IL-27/Lag3 axis in regulating Foxp3+ regulatory T cell function (2R01AI125247-07A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10797288. Licensed CC0.

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