# Identification of Adipose Tissue Factors that Induce Regulatory iNKT Cells

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $22,658

## Abstract

Project Summary: Invariant natural killer T (iNKT) cells are innate-like αβ T cells that use conserved T cell
receptor (TCR) rearrangements to recognize lipid antigens in the context of the major histocompatibility
complex (MHC) I-like molecule CD1d. Analogous to the classical Th1, Th2, and Th17 helper T cell subsets,
NKT1, NKT2, and NKT17 cells have been described with stereotypical cytokine production profiles,
transcription factor expression, and tissue localization. The vast majority of iNKT cells in C57BL/6 mice are
NKT1 cells, which reside in the liver and spleen and produce high amounts of IFNγ and IL-4 when activated by
a combination of TCR and innate cytokine signals.
 Many reports have described iNKT cells in the context of proinflammatory immune responses where
they respond to danger signals and microbial lipid antigens to mediate host defense. In contrast, we recently
identified a distinct role of iNKT cells in adipose tissues of mice and humans where they display a unique
regulatory phenotype. Maintenance of the non-inflammatory state in adipose tissue is essential to preserve
insulin sensitivity, prevent diabetes, and control obesity. We found that adipose iNKT cells produce high levels
of IL-2 that drives the expansion of adipose Tregs and IL-10 that drives M2 macrophage expansion. These
iNKT cell functions contribute significantly to the anti-inflammatory adipose microenvironment, and in the
absence of iNKT cells mice are prone to obesity and diabetes. Furthermore, specific activation of adipose iNKT
cells with the lipid antigen α-galactosylceramide (αGalCer) induces weight loss and ameliorates many
metabolic abnormalities caused by obesity. Interestingly, adipose iNKT cells have a distinct transcriptional
profile and lack expression of the PLZF transcription factor, which is expressed in iNKT cells in all other
organs. Instead, they express the transcription factor E4BP4 that drives their production of IL-10.
 We have several lines of evidence to indicate that the regulatory properties of adipose iNKT cells are
induced by exposure to the adipose microenvironment. The goal of this proposal is to identify components
of adipose tissue that drive the unique regulatory phenotype of adipose iNKT cells. In line with this goal,
we propose to first characterize the ability of adipose tissue to induce and maintain the regulatory iNKT cell
phenotype in vivo using adoptive transfer experiments (Aim 1). Then, we will analyze the contribution of
adipocyte CD1d expression to the phenotype of adipose iNKT cells (Aim 2). Finally, we will identify molecules
released by adipose tissue induce E4BP4 expression in iNKT cells and endow them with regulatory capacity
(Aim 3). Combined, these studies will identify environmental and molecular inducers of regulatory iNKT cells
that will 1) reveal new pathways to target these cells in autoimmune diseases and 2) offer insight into the
biology of an adipose-resident immune cell population that can be manipulat...

## Key facts

- **NIH application ID:** 9872983
- **Project number:** 5F31AI138353-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Nelson Martin LaMarche
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,658
- **Award type:** 5
- **Project period:** 2018-03-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872983

## Citation

> US National Institutes of Health, RePORTER application 9872983, Identification of Adipose Tissue Factors that Induce Regulatory iNKT Cells (5F31AI138353-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872983. Licensed CC0.

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