Myeloid C-Type Lectin Receptors in Viral Recognition and Antiviral Immunity

Abstract

Recognition of viral glycans by pattern recognition receptors (PRRs) in innate immunity contributes to antiviral immune responses. C-type lectin receptors (CLRs) are PRRs capable of sensing glycans present in viral pathogens to activate antiviral immune responses such as phagocytosis, antigen processing and presentation, and subsequent T cell activation. The ability of CLRs to elicit and shape adaptive immunity plays a critical role in the inhibition of viral spread within the host. However, certain viruses exploit CLRs for viral entry into host cells to avoid immune recognition. To block CLR interactions with viral glycoproteins, antiviral strategies may involve the use of multivalent glycan carrier systems. In this review, we describe the role of CLRs in antiviral immunity and we highlight their dual function in viral clearance and exploitation by viral pathogens.

Keywords: C-type lectin receptors; antiviral immunity; dendritic cells; glycans; immunomodulation; macrophages; viral evasion.

Figure 1

Recognition of pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and signaling motifs of myeloid C-type lectin receptors (CLRs). CLRs expressed by antigen-presenting cells (APCs) are able to recognize PAMPs present on pathogens, including bacteria, viruses, fungi and parasites; and DAMPs in damaged host cells. Recognized ligands cover a vast type of glycan structures, such as fucose, mannose, β-glucan, galactose, GlcNAc, but also non-glycan ligands such as monosodium urate. Upon CLR engagement, a signaling cascade is initiated through binding of early adaptors and the recruitment of kinases or phosphatases. Myeloid CLRs can be subdivided in four distinct groups according to their cytoplasmic signaling motifs and early adaptors: (A) hemi-immunoreceptor tyrosine-based activating motif (hemITAM)-coupled; (B) ITAM-coupled; (C) immunoreceptor tyrosine-based inhibitory motif (ITIM)-coupled; and (D) ITAM-ITIM independent CLRs.

Figure 2

CLRs present on the surface of dendritic cells (DCs) recognize viral antigens to trigger APC activation and subsequent T cell stimulation. Upon binding, endocytosis will take place, resulting in the internalization of the antigens. Further processing in endosomes and lysosomes results in fragmented peptides that are loaded on major histocompatibility complex (MHC) class II and MHC class I molecules for efficient priming of CD4⁺ and CD8⁺ T cells, respectively. Two signals are required for T cell activation by DCs. First, the T-cell receptor (TCR) recognizes MHC/peptide complexes. Second, the costimulatory molecules CD80/CD86 interact with CD28 expressed by the T cell. In addition, DCs express and secrete cytokines. The combination of these signals determines the fate of the activated T cell.

Figure 3

Human immunodeficiency virus type 1 (HIV-1) capture and transmission by DCs. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non integrin (DC-SIGN) present at the surface of DCs neutralizes HIV-1 by virion uptake and signalosome-mediated cytokine production and degradation of virions. Fragmented peptides are loaded on MHC class II molecules for antigen presentation to CD4⁺ T cells in order to prime T cell effector functions and induce an adaptive immune response against the virus. DC-SIGN establishment of a DC-T-cell interaction is accomplished through transient binding to intercellular adhesion molecule (ICAM)-3. However, DC-SIGN is also exploited by HIV-1 for evasion of the immune response by maintenance of intact virions in non-lysosomal endosomes. These virions undergo exocytosis and can infect CD4⁺ T cells in a process called trans-infection. Trans-infection can also occur without HIV-1 virion internalization. Additional subversion strategies of HIV-1 encompass augmented viral replication via the DC-SIGN signalosome and triggering of DC apoptosis via apoptosis signal-regulating kinase 1 (ASK-1).

Figure 4

CLRs in antiviral immunity: roles in viral clearance or as targets for viral exploitation. Surface glycoproteins in different enveloped viruses possess glycan moieties (highlighted area), mainly N-linked glycans, that are recognized by CLRs and lead to CLR-mediated endocytosis by APCs. Once inside the host cell, viruses may hijack the host’s cellular machinery to ensure viral spreading (left). HIV-1 interaction with DC-SIGN promotes trans-infection of T cells and tampers with signaling cascades to promote viral replication or to induce apoptosis of professional APCs to enhance viral infectivity. A different type of exploitation is mediated by viruses, such as DV, through interaction with myeloid DAP-12 associating lectin (MDL-1). In this case, viruses elicit an exacerbated pro-inflammatory response, that damages host cells and increases the susceptibility for viral infection. However, CLRs also have important functions in the clearance of viral infections (right). For instance, langerin captures viruses and directs them towards specialized degradation organelles called Birbeck granules. Langerin is also responsible for priming CD4⁺ and CD8⁺ T cells and to limit viral spread.