CD1a is a transmembrane protein that belongs to the CD1 family and plays an important role in the immune system. The CD1 family includes CD1a, CD1b, CD1c, and CD1d, which are closely related to antigen presentation and T cell immune responses. Compared with the classic major histocompatibility complex (MHC), CD1 plays a unique role in antigen presentation, particularly in T cell immune responses induced by lipid antigens.
(Data source: Moody's DB, et al. Curr Opin Immunol. 2017)
The structure of CD1a:
The CD1a protein consists of three extracellular domains of heavy chains (a1 , a2 , and a3), a transmembrane domain and a C-terminal cytoplasm, which non-covalently bind to β2m microglobulin. The a1 and a2 domains contain non-polar amino acids, forming a narrow and deep antigen-binding groove. These groove characteristics are particularly suitable for binding lipid peptides. The groove has two pockets A' and F'. A' is longer and narrower than F' and is covered with a roof-like structure that separates it from the protein surface. F' connects A' to the outer surface, close to the T cell receptor (TCR) recognition region.
(Data source: Moody's DB, et al. Curr Opin Immunol. 2017)
Regulation of immune response:
CD1a specifically recognizes a variety of autologous and exogenous lipids. Most antigens presented by CD1a are endogenous lipid metabolites that bind to CD1a, but it can also bind to free fatty acid neoantigens. T cells interact with CD1a cells in three constrained ways.
The first is called "head group recognition,"whereby the TCR specifically recognizes the protruding polar headform in lipid antigens, forming a ternary lipid-CD1a-TCR complex;
The second approach is called "no interference,"where some headless lipids are completely buried in the antigen-binding groove, giving the TCR the opportunity to bind directly to the top of CD1a. In this case, the TCR does not need to interact with the antigen.
The third pathway is mediated by certain nonpermissive lipids, whose polar head groups block the interaction between TCR and CD1a, preventing autoimmune responses in non-inflammatory settings.
(Data source: Yoo HJ, et al. Mol Cells. 2021)
CD1a-related diseases:
CD1a is widely used as a marker for Langerhans cells. Its high expression in normal skin tissue suggests the important role of lipid antigens in skin homeostasis. High CD1a expression on skin-resident Langerhans cells and dendritic cells supports the normal physiological role of CD1a -dependent T cell activation in human skin, regulating lipid homeostasis. The increased expression of CD1a+ DC subsets during inflammation, as well as the elevated CD1a expression in atopic dermatitis, may contribute to the increased activation of CD1a-reactive T cell populations in inflammatory skin diseases.
(Data source: de Jong A, et al. Mol Immunol. 2021)
CD1a-restricted T cells cause inflammatory skin diseases, including atopic dermatitis, psoriasis, allergic contact dermatitis, and wasp/bee venom allergy, but the identity of their immunodominant self-lipid antigens and how they are recognized remain unresolved. Further research is needed to understand the latest mechanisms of CD1a-reactive T cell biology and their potential roles in disease.
