Key Points
TCR β variable gene 4-1 (TRBV4-1) is overrepresented among CD1b-specific T cells.
The association between TRBV4-1 usage and CD1b is independent of lipid Ag.
CD1b residue E80 is essential for binding of TRBV4-1–utilizing TCRs.
Abstract
High-throughput TCR sequencing allows interrogation of the human TCR repertoire, potentially connecting TCR sequences to antigenic targets. Unlike the highly polymorphic MHC proteins, monomorphic Ag-presenting molecules such as MR1, CD1d, and CD1b present Ags to T cells with species-wide TCR motifs. CD1b tetramer studies and a survey of the 27 published CD1b-restricted TCRs demonstrated a TCR motif in humans defined by the TCR β-chain variable gene 4-1 (TRBV4-1) region. Unexpectedly, TRBV4-1 was involved in recognition of CD1b regardless of the chemical class of the carried lipid. Crystal structures of two CD1b-specific TRBV4-1+ TCRs show that germline-encoded residues in CDR1 and CDR3 regions of TRBV4-1–encoded sequences interact with each other and consolidate the surface of the TCR. Mutational studies identified a key positively charged residue in TRBV4-1 and a key negatively charged residue in CD1b that is shared with CD1c, which is also recognized by TRBV4-1 TCRs. These data show that one TCR V region can mediate a mechanism of recognition of two related monomorphic Ag-presenting molecules that does not rely on a defined lipid Ag.
Footnotes
This work was supported by the Australian Research Council (ARC) and National Health and Medical Research Council (NHMRC), the National Institutes of Health (Grants AI049313, AR048632, and AI111224), and the Netherlands Organization for Scientific Research. S.G. is an NHMRC Senior Research Fellow. J.R. is supported by an ARC Laureate Fellowship.
The online version of this article contains supplemental material.
- Received July 29, 2019.
- Accepted October 9, 2019.
- Copyright © 2019 by The American Association of Immunologists, Inc.