# Role of secreted phospholipase A2 in the activation of human CD1-restricted T cells

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $345,708

## Abstract

PROJECT SUMMARY
CD1 proteins are structurally related to MHC class I, but instead of peptides, they present lipid antigens to T
cells. We and others have shown that CD1-restricted T cells recognizing self-lipids are abundant in the human
T cell repertoire, yet it remains unclear how the activation of these T cells is regulated in vivo. Overt reactivity to
self-lipids suggests that antigenic CD1-lipid complexes must be tightly regulated in order to prevent continuous
T cell stimulation. Both fatty acids and lysophosphatidylcholine (LPC) have been identified as antigens for certain
human CD1-restricted T cells. These lipids are released when the enzyme phospholipase A2 (PLA2) acts on
membrane phospholipids, supporting a role for PLA2 activity in the generation of CD1 self antigens. Since
secreted PLA2 (sPLA2) is increased in response to tissue damage and infections, we hypothesize that sPLA2
activity in humans is a common mechanism through which the activation of CD1-restricted T cells is regulated,
by temporarily increasing the availability of CD1 self-lipid antigens. This is supported by our preliminary
observations that PLA2 activity on antigen presenting cells results in CD1-dependent T cell activation in healthy
individuals. Furthermore, since sPLA2 levels are constitutively elevated in many chronic inflammatory conditions,
including rheumatoid arthritis, asthma, atherosclerosis and psoriasis, this mechanism may underlie persistent T
cell activation in these conditions through continued high levels of self lipid antigens. In this proposal we will
systematically investigate the link between sPLA2 activity and activation of lipid-specific T cell populations, and
characterize the human CD1-restricted T cell populations that respond to PLA2-derived phospholipid breakdown
products. Using T cell cultures and a human skin explant model, we will determine if PLA2 activity induces the
activation/expansion of lysophospholipid-reactive T cell populations. We will investigate the breadth of the human
lysophospholipid-specific T cell repertoire, and its specificity/promiscuity. For this we use a panel of
lysophospholipid-loaded CD1 tetramers, and a CD1 plate assay. Last, we will apply combined single cell TCR
sequencing and functional phenotyping to CD1-LPC tetramer+ T cells isolated from healthy donors and psoriasis
patients, to determine if these populations primarily have pro-inflammatory or immunoregulatory functions, and
whether clonal expansions occur in the context of inflammatory skin disease. This proposal will provide insight
in whether sPLA2 activity is a significant driver of human CD1-restricted T cell activation, and will elucidate the
specificities and functions of the responding T cell populations. Because sPLA2 activity is central to both acute
and chronic inflammation, results from this study will lead to a better understanding of a common physiological
pathway through which T cells can be activated in multiple distinct inflammatory condi...

## Key facts

- **NIH application ID:** 9891016
- **Project number:** 5R01AR074037-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Annemieke de Jong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,708
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891016

## Citation

> US National Institutes of Health, RePORTER application 9891016, Role of secreted phospholipase A2 in the activation of human CD1-restricted T cells (5R01AR074037-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891016. Licensed CC0.

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