Current Understanding of the Roles of CD1a-Restricted T Cells in the Immune System

Abstract

Cluster of differentiation 1 (CD1) is a family of cell-surface glycoproteins that present lipid antigens to T cells. Humans have five CD1 isoforms. CD1a is distinguished by the small volume of its antigen-binding groove and its stunted A' pocket, its high and exclusive expression on Langerhans cells, and its localization in the early endosomal and recycling intracellular trafficking compartments. Its ligands originate from self or foreign sources. There are three modes by which the T-cell receptors of CD1a-restricted T cells interact with the CD1a:lipid complex: they bind to both the CD1a surface and the antigen or to only CD1a itself, which activates the T cell, or they are unable to bind because of bulky motifs protruding from the antigen-binding groove, which might inhibit autoreactive T-cell activation. Recently, several studies have shown that by producing T_H2 or T_H17 cytokines, CD1a-restricted T cells contribute to inflammatory skin disorders, including atopic dermatitis, psoriasis, allergic contact dermatitis, and wasp/bee venom allergy. They may also participate in other diseases, including pulmonary disorders and cancer, because CD1a-expressing dendritic cells are also located in non-skin tissues. In this mini-review, we discuss the current knowledge regarding the biology of CD1a-reactive T cells and their potential roles in disease.

Keywords: CD1 molecules; CD1a; inflammatory skin diseases; lipid antigens; lipid-reactive T cells.

Fig. 1. Schematic representation of CD1a and modes by which T cell receptors interact with the CD1a-lipid complex.

(A) The structural feature of CD1a. The heavy chain consists of three domains (α1, α2, α3) with a short cytoplasmic tail, and it is non-covalently associated with a light chain (β2m). The α1 and α2 domains form the lipid antigen-binding groove, which bears two pockets, A′ and F′. (B) TCRs recognize CD1a-lipid complexes by three modes: head-group recognition (upper), absence of interference (middle) and interference (bottom). 1) Some TCRs interact with a specific head-group of lipids protruding out of the CD1a and form a ternary lipid-CD1a-TCR complex. 2) Some headless lipids are completely buried within antigen binding groove and allow TCRs the opportunity to directly bind to the A roof of CD1a. In this case, TCRs do not need interact with antigens, but CD1a itself. 3) Bulky head-groups of some lipids can interfere TCR:CD1a interaction, thereby controlling the activation of CD1a-autoreactive T cells. β2m, β2-microglobulin.

Fig. 2. Overview of antigen presentation by CD1a and roles of CD1a-reactive T cells in diseases.

CD1a-expressing APCs are abundant, but not limited, in skin. Antigens of CD1a are derived from self or various foreign sources such as Mycobacteria, plants and cosmetics, and presented on CD1a in early/recycling endosomal compartments or at cell surface. Similar to the origins of antigens, host- or foreign-derived PLA₂ can generate neoantigens of CD1a under certain conditions. CD1a-reactive T cells activated by recognizing the complex of CD1a and antigen or CD1a itself produce various cytokines, thereby controlling immune responses occurred in inflammatory skin diseases such as contact dermatitis, psoriasis and atopic dermatitis.