Human skin is colonized by T cells that recognize CD1a independently of lipid
- J Clin Invest. 2021 Jan 4;131(1):e140706. doi: 10.1172/JCI140706.
- 1. Graduate Program in Immunology, Harvard Medical School, Boston, Massachusetts, USA.
- 2. Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
- 3. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
- 4. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
- 5. Division of Plastic and Reconstructive Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston Massachusetts, USA.
- 6. NIH Tetramer Core Facility, Emory University, Atlanta, Georgia, USA.
- 7. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
- 8. Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
- 9. Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA.
- 10. MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, United Kingdom.
- 11. School of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- 12. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, United Kingdom.
- 13. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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 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.