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Review
. 2022 Jul 15;14(1):4-16.
doi: 10.1093/procel/pwac012. eCollection 2023 Jan.

Tinker, tailor, soldier, cell: the role of C-type lectins in the defense and promotion of disease

James N Arnold  1 , Daniel A Mitchell  2
Affiliations
Review

Tinker, tailor, soldier, cell: the role of C-type lectins in the defense and promotion of disease

James N Arnold et al. Protein Cell. .

Abstract

C-type lectins (CTLs) represent a large family of soluble and membrane-bound proteins which bind calcium dependently via carbohydrate recognition domains (CRDs) to glycan residues presented on the surface of a variety of pathogens. The deconvolution of a cell's glycan code by CTLs underpins several important physiological processes in mammals such as pathogen neutralization and opsonization, leukocyte trafficking, and the inflammatory response. However, as our knowledge of CTLs has developed it has become apparent that the role of this innate immune family of proteins can be double-edged, where some pathogens have developed approaches to subvert and exploit CTL interactions to promote infection and sustain the pathological state. Equally, CTL interactions with host glycoproteins can contribute to inflammatory diseases such as arthritis and cancer whereby, in certain contexts, they exacerbate inflammation and drive malignant progression. This review discusses the 'dual agent' roles of some of the major mammalian CTLs in both resolving and promoting infection, inflammation and inflammatory disease and highlights opportunities and emerging approaches for their therapeutic modulation.

Keywords: C-type lectins; DC-SIGN; MBL; arthritis; cancer; infection; selectins.

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Figures

Figure 1.
Figure 1.
CTL structures. A cartoon representation of the domain structure of CTLs and CTLRs discussed in this review. The collagen like domains depict the triple coiled helix of three individual subunits that then associate to form higher order oligomers. CRD, carbohydrate recognition domain; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; EGF, epidermal growth factor; SCR, short consensus repeat domains; MBL, mannose-binding lectin; MASPs, MBL-associated serine proteases; MMR, macrophage mannose receptor; SP-A/D, surfactant protein A/D. The image is not drawn to scale. Created using BioRender.com.
Figure 2.
Figure 2.
Structure of siaylated and un-sialylated Lewis x/a glycan epitopes. Sugar residue arrangement and the respective linkages shown to create the SLex/a and Lex/a structures. These epitopes can be displayed on both N- and O-linked sugars, lipid or protein at the “R” position. The minimal glycan epitope for SLe structure is a sialic acid residue α2,3-linked to galactose with a fucose α1,3-linked (SLex) or α1,4-linked (SLea) to GlcNAc. Le structures do not have the terminal sialic acid. Neu5Ac, N-acetylneuraminic acid (sialic acid); Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; Man, mannose. The glycans are drawn in accordance with GlycanBuilder (Damerell et al. 2012).
Figure 3.
Figure 3.
Lectin pathway of complement activation. MBL binding to cellular glycans results in the autoactivation of MASP-2 which cleaves C4 to expose a thioester group (not shown but detailed chemistry is presented by Dodds et al. (1996) which allows fragment C4b to covalently bind to proteins and cell membranes in the local vicinity, facilitating its accumulation on the cell surface. C2 subsequently binds C4b and is subsequently cleaved by MASP-2 to form the C3 convertase C4b2a. The C3 convertase then cleaves C3 which exposes its hidden thioester group (not shown) to allow the fragment C3b to accumulate on the cell surface. C3b is further cleaved to form iC3b which is a potent opsonin. Activation of C3 also leads to the formation of the membrane attack complex through the formation of a C5 convertase consisting of C4b2a3b which cleaves C5 which binds to the cell surface and forms a scaffold which associates with C6-9 for the formation of the membrane attack complex which consists of a pore of polymerized C9 which leads to cell lysis. MBL, mannose-binding lectin; MASPs, MBL-associated serine proteases. Created using BioRender.com.
Figure 4.
Figure 4.
The glycoforms of IgG. Diagram (left) shows the structure of IgG highlighting the approximate location of the heavy chain N-linked glycosylation site at Asn-297 in the Fc region (red dash). The predominant glycan structures that occupy the Asn-297 site on each heavy chain are displayed (right top) and form the basis of the IgG-G0, -G1, -G2 nomenclature based on the number of terminal galactose residues. The glycans shown may also vary by the presence of absence of a core fucose (R1) and/or bisecting GlcNAc (R2) and/or sialic acid (R3) (right bottom). Asn, Asparagine; Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; IgG, immunoglobulin G. The glycans are drawn in accordance with GlycanBuilder (Damerell et al. 2012). IgG was created using BioRender.com.
Figure 5.
Figure 5.
The steps of leukocyte extravasation from the blood. Diagram showing the key steps and interactions associated with leukocyte extravasation (from left to right). Inflammatory stimuli from the tissue such as TNF, IL-1β, and LPS activate the endothelium to express high levels of E- and P-selectin which act to tether/capture leukocytes from the blood via SLex/a epitopes presented on leukocyte glycoproteins. This initiates leukocyte rolling via these CTL interactions. Leukocytes then become activated in response to chemokines and other chemoattractants being released from the inflammatory site which activates β2-integrins that adopt a structural change that allows more efficient interactions with endothelial VCAM-1 and ICAM-1 permitting firm attachment and arrest. Subsequently, this leads to a slow crawling of the leukocyte prior to transendothelial migration into the tissue. ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1β; LPS, lipopolysaccharide; TNFα, tumor necrosis factor-α, VCAM-1, vascular cell adhesion molecule-1. Created using BioRender.com.
Figure 6.
Figure 6.
The diverse roles of CTLs in the defense and promotion of disease. Diagram summarizing the key axes discussed in the review depicting the role of CTLs and their ‘double agent’ roles in both pathogen and host glycoprotein interactions and the defense and promotion of pathogen, inflammation and inflammatory disease. Centre image is taken from Fig. 1. BCR, B cell receptor; Fab, Ig antigen-binding region; FL, follicular lymphoma; IgG/A/M, immunoglobulin-G/A/M. Created using BioRender.com.
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