Immunity system complexity: how lipids help (Introduction)

by David Turell , Monday, November 27, 2023, 20:22 (151 days ago) @ David Turell

New lipid research:

https://www.the-scientist.com/news/move-over-proteins-exploring-lipids-in-adaptive-immu...

"The immune system discriminates between the body’s own cells and foreign invaders largely by auditing proteins. Cells digest proteins into short fragments and load them onto the major histocompatibility complex (MHC), which presents the peptide to T cells for inspection. Using a parallel strategy, cells can also present lipids to T cells via a protein called cluster of differentiation 1 (CD1). Although scientists knew of the existence of lipid antigens, most immunology research has focused on protein antigens, leaving much to demystify about the role of CD1 and lipids.

"In a study spanning 14 years, a team of immunologists took on the challenge of characterizing CD1. Published in the journal Cell, they showed that CD1 can onboard hundreds of lipids to present to T cells.

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"Lipid structures are harder to uncover, and past studies have focused on individual CD1 types rather than the whole ensemble, which includes four different variants (CD1a to CD1d), making comparisons difficult. In this study, “we have all four proteins together that allow us to figure the patterns that belong to each specific isoform,” said Shouxiong Huang, coauthor and immunologist at the University of Cincinnati.

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"Only a small number of lipids were known to bind CD1, but the new lipidomic analysis increased the count to more than 1600.4 Moreover, all four CD1 types shared more than half of the lipids, an overlap Barral hypothesized might boost the immunosurveillance capabilities of T cells. “Even if it’s the same lipid, it doesn’t necessarily sit in the same way in the different CD1 molecules,” she speculated. “This will affect what the T cell receptor sees.”

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"The team found that CD1 varieties preferentially loaded some lipids according to chain length. For example, CD1a preferred shorter chains (38 to 40 carbons) than CD1d (42 to 46 carbons). Of particular interest to the researchers was CD1b, a molecule that preferred short lipids with a chain length of 30 to 38 carbons even though its groove is large enough to hold twice that size. This led the team to hypothesize that the CD1b groove could hold two short lipids simultaneously. By resolving the crystal structure of the CD1b-lipid complex, they found that two lipids occupied the upper and lower chambers of the groove, suggesting that only the upper lipid contacts the T cell receptors (TCR).

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"These lipid antigens originate from human cells and might serve to train T cells to discriminate the body’s own lipids from those of infectious microbes. Moody noted that some of these lipids might influence the immune response in autoimmune conditions or cancer, too. Alternatively, a few might have no immune role but serve as placeholders in the hydrophobic, water-repelling groove until a lipid antigen is loaded. Some of the most frequently loaded lipids might include placeholders, like derivates of sphingomyelin and phosphatidylcholine, but the team couldn’t find a single dominant lipid, implying that a variety plug the groove.

Comment: an important new area of discovery in the immune system. T cells remain as a key center for response. We see a new way they are informed in the design.