Lipid regulation of T cell receptor transmembrane signaling
Biochemistry
Final Report Abstract
Immunotherapies against cancer, that are based on T cells expressing chimeric antigen receptors (CARs), have received unprecedented success in treating cancers. However, their applications are limited, which calls for more mechanistic studies of T cell activation. As a major receptor on the T cell surface, the T cell receptor (TCR) recognizes antigen and delivers the activation signal to the cell. Previous works from the Prof. Xu and Prof. Schamel research groups have shown that membrane lipids can regulate TCR signaling, but the underlying molecular mechanisms are not well understood. In this joint Sino-German project, we have combined the expertises from both labs and show that the lipids cholesterol and ceramide modulate TCR signalling in T cells. We have solved the structure of the binding of cholesterol to the isolated TCRβ chain, showing that cholesterol binds in a reverse orientation in which its hydrophilic OH group is located to the middle of the membrane bilayer, binding to a central lysine in the transmembrane region of TCRβ. Cholesterol sulfate bound in the same manner, explaining how it competes with cholesterol in binding to TCRβ. We show that cholesterol reduces and cholesterol sulfate increases TCR signalling. Thus, the head group of this steroid lipid determines its activity at the TCR. We also studied the lipid ceramide and found that ceramide decreases TCR nanoclustering and thus the activation of memory T cells. Together, these examples how that the lipid composition of the membrane can regulate TCR signalling. Finally, we used our knowledge and engineered new CARs for cancer immunotherapy. A new CAR that contains the cytosolic tail of CD3ε (BBε) outperformed the FDA-approved CAR with the ζ cytosolic tail in killing of tumour cells. Important for the increased function of the BBε CAR were the lipid-binding basic-rich sequence and the Lck-binding receptor kinase motif. Thus, there is a potential that the new BBε developed in this project could improve CAR T-cell based cancer immunotherapies.
Publications
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CCR 5 deficiency impairs CD 4 + T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis. The EMBO Journal, 39(15).
Martín‐Leal, Ana; Blanco, Raquel; Casas, Josefina; Sáez, María E.; Rodríguez‐Bovolenta, Elena; de Rojas, Itziar; Drechsler, Carina; Real, Luis Miguel; Fabrias, Gemma; Ruíz, Agustín; Castro, Mario; Schamel, Wolfgang WA; Alarcón, Balbino; van Santen, Hisse M. & Mañes, Santos
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αβ and γδ T cell receptors: Similar but different. Journal of Leukocyte Biology, 107(6), 1045-1055.
Morath, Anna & Schamel, Wolfgang W.
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Cholesterol Binds in a Reversed Orientation to TCRβ-TM in Which Its OH Group is Localized to the Center of the Lipid Bilayer. Journal of Molecular Biology, 433(24), 167328.
Wu, Hongyi; Cao, Ruiyu; Wei, Shukun; Pathan-Chhatbar, Salma; Wen, Maorong; Wu, Bin; Schamel, Wolfgang W.; Wang, Shuqing & OuYang, Bo
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Direct Regulation of the T Cell Antigen Receptor's Activity by Cholesterol. Frontiers in Cell and Developmental Biology, 8.
Pathan-Chhatbar, Salma; Drechsler, Carina; Richter, Kirsten; Morath, Anna; Wu, Wei; OuYang, Bo; Xu, Chenqi & Schamel, Wolfgang W.
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The role of cholesterol in TCR signalling in autoimmune diseases. Medical Research Archives, 9(2).
Pathan-Chhatbar, Salma; Chevalier, Nina; Voll, Reinhard & Schamel, Wolfgang
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Chimeric antigen receptors, vectors coding for such receptors and their use in the modification of T cells. WO0202193506, EP3715368A1
Schamel W.W., Minguet S. & Hartl F.
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Kidins220 and Aiolos promote thymic iNKT cell development by reducing TCR signals. Science Advances, 10(11).
Herr, Laurenz A.; Fiala, Gina J.; Sagar, NA; Schaffer, Anna-Maria; Hummel, Jonas F.; Zintchenko, Marina; Raute, Katrin; Velasco, Cárdenas Rubí M.-H.; Heizmann, Beate; Ebert, Karolina; Fehrenbach, Kerstin; Janowska, Iga; Chan, Susan; Tanriver, Yakup; Minguet, Susana & Schamel, Wolfgang W.
