Background:
CD1a is an MHC I-like molecule expressed on a subset of monocytes as well as Langerhans cells in human skin, and presents a wide array of lipid antigens to T cells. The CD1a-reactive T cells are abundant in human skin and play important roles in skin homeostasis and inflammatory responses such as atopic dermatitis, psoriasis, and contact hypersensitivity. However, the interplay between responding T cell repertoire and CD1a remain unclear, limiting the understanding of the CD1a-mediated immunity.
Methods:
This work has integrated multi-disciplinary approaches including immune T cell analysis using CD1a tetramers, the biochemical characterization of interactions between T-cell receptor (TCR) and CD1a using surface plasmon resonance analyses, together with structural biology to understand the molecular basis of TCR recognition of self-lipid displaying CD1a.
Results and significance:
Here, we analysed the ab TCR repertoire of CD1a presenting self-lipids derived from human PBMC. TCR repertoire analysis revealed a biased TCR gene usage and a new TCR motif of CD1a-restricted reactive T cells in humans. We confirm the specificity of TCR and CD1a interactions is lipid antigen independent and the affinities between responding TCR and CD1a are relatively strong, falling within low micromolar range. X-ray crystal structure analysis of the TCR-CD1a complex revealed the TCR docking modality at the A’ roof of CD1a and that an inter-donor (or public) conserved motif within the CDR 3 alpha loop plays a critical role in CD1a recognition. Overall, our study describes the principles governing recognition and response by an autoreactive TCR, as well as key determinants for CD1a specificity. Thus, we have advanced the understanding of the molecular mechanism of TCR-mediated recognition of CD1a by a population of autoreactive T cells that is shared amongst different individuals and may have important implications for autoimmunity, highlighting the translational therapeutic opportunities for targeted immunotherapy.