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 conditions, and provide novel insights in modes through which lipid-specific T cell activation may be regulated therapeutically.

Public Health Relevance

Inflammation is central to many chronic conditions, including rheumatoid arthritis, asthma, atherosclerosis and inflammatory skin disease. Increased levels of secreted phospholipase A2 are observed in these conditions, resulting in cleavage of membrane phospholipids into lysophospholipids and fatty acids. In this proposal, we investigate the recognition of these phospholipid breakdown products by T cells, which will open up avenues of investigation into the functions of lipid-specific T cells in the context of inflammation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Cibotti, Ricardo
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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