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

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $397,500

## Abstract

Abstract
Foxp3+ CD4 T cells (Tregs) play a key role in regulating immunity and tolerance. Defects in Treg
generation and/or functions are directly associated with uncontrolled immune activation leading to the
development of autoimmune diseases. Yet, the precise mechanisms by which Tregs express the
functions remain unclear. Multiple sclerosis (MS) is a myelin antigen specific autoimmune
inflammation of the central nervous system (CNS) mediated by myelin antigen specific Th17 type CD4
T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model that shares clinical
and histological features with MS, and is widely used to investigate the pathogenesis as well as to
develop an approach to treat the disease. Increasing evidence suggests that Treg function may be
dysregulated in MS patients or EAE bearing mice. Thus, identifying pathways that improve Treg
function is an issue of clinical importance to develop a potential therapy targeting Tregs. The major
goal of this application is to test the role of IL-27 in Treg function. We recently reported that IL-27
signaling in Tregs plays an essential role in suppressing Th17 type inflammation in the intestine. We
utilized a newly developed Treg-specific Il27ra-/- animal and found that Treg-specific IL-27R deficiency
results in a severe EAE. CNS infiltrating CD4 T cells producing proinflammatory cytokines were
uncontrolled in the presence of Il27ra-/- Tregs, while IL-10+ CD4 T cells implicated in regulation of
inflammatory responses remained unchanged. Genome wide microarray analysis revealed that IL-27
stimulation in Tregs induces Lag3, a CD4 like molecule implicated in negative regulation of T cell
activation. We then used a novel Treg-specific Lag3-/- animal and found that they also develop severe
EAE, suggesting that Treg expression of Lag3 may be critical to mediate IL-27-induced Treg function.
Finally, IL-27 prestimulation in Tregs significantly enhances suppressive function both in vitro and in
vivo. The overall hypothesis is that IL-27 controls Treg suppressive function during EAE and that Lag3
induced by IL-27 signaling plays a key role in mediating IL-27 effect on Tregs. We also propose that
the suppressive function of Tregs can be improved by IL-27 prestimulation, reversing ongoing
inflammation in the CNS. Three specific aims are proposed. Aim #1 will test the role of IL-27 signaling
on Treg function during EAE. Aim #2 will test To test the role of Lag3 during IL-27-mediated control of
Treg function. Aim #3 will test the mechanisms by which IL-27 prestimulated Tregs efficiently reverse
ongoing neuroinflammation. We anticipate that the results from this study will identify novel
mechanisms by which IL-27 modulates Treg function via Lag3 to downregulate inflammation in the
CNS. Completing the proposed studies will provide an important basis for the development of new
strategies targeting the IL-27/Lag3 axis in Tregs to treat MS, and chronic inflammation in other
tissues.

## Key facts

- **NIH application ID:** 10264303
- **Project number:** 5R01AI125247-06
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Booki Min
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2017-03-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264303

## Citation

> US National Institutes of Health, RePORTER application 10264303, The role of IL-27/Lag3 axis in regulating Foxp3+ regulatory T cell function (5R01AI125247-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10264303. Licensed CC0.

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