Human skin is colonized by T cells that recognize CD1a independently of lipid
Cotton, Rachel N; Cheng, Tan-Yun; Wegrecki, Marcin; Le Nours, Jérôme; Orgill, Dennis P; Pomahac, Bohdan; Talbot, Simon G; Willis, Richard A; Altman, John D; de Jong, Annemieke; Ogg, Graham; Van Rhijn, Ildiko; Rossjohn, Jamie; Clark, Rachael A; Moody, D Branch
(2021) Journal of Clinical Investigation, volume 131, issue 1, pp. 1 - 15
(Article)
Abstract
CD1a-autoreactive T cells contribute to skin disease, but the identity of immunodominant self-lipid antigens and their mode of recognition are not yet solved. In most models, MHC and CD1 proteins serve as display platforms for smaller antigens. Here, we showed that CD1a tetramers without added antigen stained large T cell
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pools in every subject tested, accounting for approximately 1% of skin T cells. The mechanism of tetramer binding to T cells did not require any defined antigen. Binding occurred with approximately 100 lipid ligands carried by CD1a proteins, but could be tuned upward or downward with certain natural self-lipids. TCR recognition mapped to the outer A' roof of CD1a at sites remote from the antigen exit portal, explaining how TCRs can bind CD1a rather than carried lipids. Thus, a major antigenic target of CD1a T cell autoreactivity in vivo is CD1a itself. Based on their high frequency and prevalence among donors, we conclude that CD1a-specific, lipid-independent T cells are a normal component of the human skin T cell repertoire. Bypassing the need to select antigens and effector molecules, CD1a tetramers represent a simple method to track such CD1a-specific T cells from tissues and in any clinical disease.
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Keywords: Medicine(all)
ISSN: 0021-9738
Publisher: The American Society for Clinical Investigation
Note: Funding Information: We thank the NIH Tetramer Core Facility staff for biotinylated CD1 proteins and HLA-DRB1 monomer and matched HEK293T cells. J. Teague provided advice on human skin culture, and BWH Division of Plastic and Reconstructive Surgery clinical staff provided surgical discarded tissue. The work is supported by the NIH (R01 AR048632, R01 AI127654, P30 AR069625, T32 AR007530), the Wellcome Trust Collaborative Award in Science, the UK Medical Research Council, the NIHR Oxford Biomedical Research Centre, the National Health and Medical Research Council of Australia, and the Australian Research Council (ARC) (CE140100011). JLN is supported by an ARC Future Fellowship (FT160100074); JR is supported by an Australian ARC Laureate Fellowship. ADJ is supported by NIH K01 AR068475. Funding Information: Conflict of interest: RNC declares income from MPM Capital. GO declares laboratory research support from UCB through Oxford University. Copyright: © 2021, American Society for Clinical Investigation. Submitted: May 27, 2020; Accepted: October 14, 2020; Published: January 4, 2021. Reference information: J Clin Invest. 2021;131(1):e140706. https://doi.org/10.1172/JCI140706. Publisher Copyright: © 2021, American Society for Clinical Investigation.
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