Abstract
CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.
| Language | English |
|---|---|
| Article number | 56 |
| Number of pages | 12 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 4 Jan 2019 |
Keywords
- immune tolerance
- immunology
- structural biology
- T-cell receptor
Cite this
}
A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids. / Shahine, Adam; Reinink, Peter; Reijneveld, Josephine F.; Gras, Stephanie; Holzheimer, Mira; Cheng, Tan Yun; Minnaard, Adriaan J.; Altman, John D.; Lenz, Steffi; Prandi, Jacques; Kubler-Kielb, Joanna; Moody, D. Branch; Rossjohn, Jamie; Van Rhijn, Ildiko.
In: Nature Communications, Vol. 10, No. 1, 56, 04.01.2019.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids
AU - Shahine, Adam
AU - Reinink, Peter
AU - Reijneveld, Josephine F.
AU - Gras, Stephanie
AU - Holzheimer, Mira
AU - Cheng, Tan Yun
AU - Minnaard, Adriaan J.
AU - Altman, John D.
AU - Lenz, Steffi
AU - Prandi, Jacques
AU - Kubler-Kielb, Joanna
AU - Moody, D. Branch
AU - Rossjohn, Jamie
AU - Van Rhijn, Ildiko
PY - 2019/1/4
Y1 - 2019/1/4
N2 - CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.
AB - CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.
KW - immune tolerance
KW - immunology
KW - structural biology
KW - T-cell receptor
UR - http://www.scopus.com/inward/record.url?scp=85059503511&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07898-0
DO - 10.1038/s41467-018-07898-0
M3 - Article
VL - 10
JO - Nature Communications
T2 - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 56
ER -