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.
Original language | English |
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Pages (from-to) | 397-406 |
Number of pages | 10 |
Journal | Nature Immunology |
Volume | 19 |
Issue number | 4 |
DOIs | |
Publication status | Published - 1 Apr 2018 |
Cite this
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T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. / 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.; Van Rhijn, Ildiko; Moody, D. Branch; Rossjohn, Jamie.
In: Nature Immunology, Vol. 19, No. 4, 01.04.2018, p. 397-406.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids
AU - Wun, Kwok S.
AU - Reijneveld, Josephine F.
AU - Cheng, Tan Yun
AU - Ladell, Kristin
AU - Uldrich, Adam P.
AU - Le Nours, Jérôme
AU - Miners, Kelly L.
AU - McLaren, James E.
AU - Grant, Emma J.
AU - Haigh, Oscar L.
AU - Watkins, Thomas S.
AU - Suliman, Sara
AU - Iwany, Sarah
AU - Jimenez, Judith
AU - Calderon, Roger
AU - Tamara, Kattya L.
AU - Leon, Segundo R.
AU - Murray, Megan B.
AU - Mayfield, Jacob A.
AU - Altman, John D.
AU - Purcell, Anthony W.
AU - Miles, John J.
AU - Godfrey, Dale I.
AU - Gras, Stephanie
AU - Price, David A.
AU - Van Rhijn, Ildiko
AU - Moody, D. Branch
AU - Rossjohn, Jamie
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85043464869&partnerID=8YFLogxK
U2 - 10.1038/s41590-018-0065-7
DO - 10.1038/s41590-018-0065-7
M3 - Article
VL - 19
SP - 397
EP - 406
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
IS - 4
ER -