Wun, Kwok S., Reijneveld, Josephine F., Cheng, Tan-Yun, Ladell, Kristin, Uldrich, Adam P., Le Nours, Jérôme, Miners, Kelly L., Mclaren, James E., Grant, Emma J., Haigh, Oscar L., Watkins, Thomas S., Suliman, Sara, Iwany, Sarah, Jimenez, Judith, Calderon, Roger, Tamara, Kattya L., Leon, Segundo R., Murray, Megan B., Mayfield, Jacob A., Altman, John D., Purcell, Anthony W., Miles, John J., Godfrey, Dale I., Gras, Stephanie, Price, David A., Rhijn, Ildiko Van, Moody, D. Branch, and Rossjohn, Jamie (2018) T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nature Immunology, 19. pp. 397-406.

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Abstract

The hallmark function of αβ T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen–presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.

Item ID:	56663
Item Type:	Article (Research - C1)
ISSN:	1529-2916
Copyright Information:	© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
Funders:	US National Institutes of Health (NIH), Australian Research Council (ARC), National Health and Medical Research Council (NHMRC), Wellcome Trust (WT)
Projects and Grants:	NIH R01 AR048632, NIH R01 AI049313, NIH AI U19111224
Date Deposited:	12 Feb 2019 22:31
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 100%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 100%
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