CD1 molecules: Beyond antigen presentation

Abstract

CD1 molecules are well known for their role in binding and presenting lipid antigens to mediate the activation of CD1-restricted T cells. However, much less appreciated is the fact that CD1 molecules can have additional "unconventional" roles which impact the activation and functions of CD1-expressing cells, ultimately controlling tissue homeostasis as well as the progression of inflammatory and infectious diseases. Some of these roles are mediated by so-called reverse signalling, by which crosslinking of CD1 molecules at the cell surface initiates intracellular signalling. On the other hand, CD1 molecules can also control metabolic and inflammatory pathways in CD1-expressing cells through cell-intrinsic mechanisms independent of CD1 ligation. Here, we review the evidence for "unconventional" functions of CD1 molecules and the outcomes of such roles for health and disease.

Keywords: CD1; CD1d crosslinking; Lipid metabolism.

Fig. 1

The functions of CD1d. The CD1d-NKT axis is not unidirectional and leads to the activation of NKT cells and CD1d-expressing cells. CD1d-dependent presentation of lipids to NKT cells results in NKT cell activation, but also in the direct provision of “help” to CD1d-expressing cells. Antigen presenting cell (APC)-NKT cell interactions can be supported by the engagement of costimulatory molecules and cytokines. In addition, reverse CD1d signalling also likely contributes to APC activation. TCR, T cell receptor.

Fig. 2

Summary of CD1d functions mediated by reverse signalling following antibody crosslinking at the cell surface of various CD1d-expressing cell types. The main signalling pathways in (A) murine intestinal epithelial cells (Olszak et al., 2014), (B) human monocytes and dendritic cells (Yue et al., 2005, Lameris et al., 2016), (C) murine group 3 innate lymphoid cells (Saez de Guinoa et al., 2017) or (D) human myeloma and B lymphoblastoid cell lines (Spanoudakis et al., 2009, Lameris et al., 2016) are shown.

Fig. 3

Summary of the cell-intrinsic functions of CD1d in murine macrophages (independent of receptor ligation, antibody crosslinking or NKT cells). The main CD1d-dependent signalling pathways are shown as reported by (A)Liu et al., (2019), (B)Cui et al., (2020) and (C)Brailey et al., (2022). iGb3, Glycolipid isoglobotrihexosylceramide; TLR, Toll-like receptor.