αβ T cell receptor recognition of self-phosphatidylinositol presented by CD1b

Farquhar, Rachel, Van Rhijn, Ildiko, Moody, D. Branch, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Shahine, Adam 2023. αβ T cell receptor recognition of self-phosphatidylinositol presented by CD1b. Journal of Biological Chemistry 299 (2) , 102849. 10.1016/j.jbc.2022.102849

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Abstract

CD1 glycoproteins present lipid-based antigens to T cell receptors (TCRs). A role for CD1b in T cell-mediated autoreactivity was proposed when it was established that CD1b can present self-phospholipids with short alkyl chains (∼C34) to T cells; however, the structural characteristics of this presentation and recognition are unclear. Here we report the 1.9 Å-resolution binary crystal structure of CD1b presenting a self-phosphatidylinositol-C34:1 (PI) and an endogenous scaffold lipid. Moreover, we also determined the 2.4 Å structure of CD1b-PI complexed to an autoreactive αβ TCR, BC8B. We show the TCR docks above CD1b and directly contacts the presented antigen, selecting for both the phosphoinositol headgroup and glycerol neck region via antigen remodelling within CD1b and allowing lateral escape of the inositol moiety through a channel formed by the TCR α-chain. Furthermore, through alanine scanning mutagenesis and surface plasmon resonance, we identified key CD1b residues mediating this interaction, with Glu-80 abolishing TCR binding. We additionally define a role for both CD1b α1 and α2 molecular domains in modulating this interaction. These findings suggest the BC8B TCR contacts both the presented phospholipid and the endogenous scaffold lipid via a dual mechanism of co-recognition. Taken together, these data expand our understanding into the molecular mechanisms of CD1b-mediated T cell autoreactivity.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2022-12-28
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Date of First Compliant Deposit:	6 January 2023
Date of Acceptance:	23 December 2022
Last Modified:	04 May 2023 05:06
URI:	https://orca.cardiff.ac.uk/id/eprint/155483

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