DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway

Abstract

Dendritic cell immunoreceptor (DCIR) is IntroductionIt is known that cell-free virions do not efficiently cross genital epithelial cells. Instead HIV-1 uses primarily dendritic cells (DCs) to penetrate the mucosal epithelium. 1,2 The virus is then transferred and disseminated from this entry site to T-cell zones in secondary lymphoid organs, where it can productively infect residing CD4 ϩ T cells. The infection process causes a marked depletion of CD4 ϩ T cells, 3 progressive impairment of the immune system, as well as chronic hyperactivation of both CD4 ϩ and CD8 ϩ T cells. 4 The initial attachment step of HIV-1 to DCs may occur through several complex interactions between the virus and the target cell surface (reviewed in Clapham and McKnight 5 and in Ugolini et al 6 ) such as the association between the oligosaccharides found on the external envelope glycoprotein gp120 and the mannose receptor (CD206), langerin (CD207), or 8 This will result in virus capture and transmission to CD4 ϩ T cells in an effective trans mode 9 (ie, transfer of virions bound onto DCs and/or localized in endosomes). Another lectin receptor, that is, the dendritic cell immunoreceptor (DCIR), can behave as an HIV-1 attachment factor for HIV-1 to participate actively in trans infection of CD4 ϩ T cells. 10 DCIR also contributes to cis-infection events, that is, infection of surrounding CD4 ϩ T cells by virions produced by DCs productively infected with HIV-1. 10 DCIR is a member of a recently described family of C-type lectin receptors (CLRs), which includes DCAR, dectin-2, BDCA-2, MCL, and MINCLE. These receptors carry a single carbohydrate recognition domain (CRD) at the COOH terminal and generally lack consensus signaling motifs in their cytoplasmic region. 11 Several members of the family, however, possess a positively charged residue in their transmembrane region, via which they associate with immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor molecules, such as the Fc receptor ␥ chains. Importantly, DCIR is the only family member harboring an immunoreceptor tyrosine-based inhibitory motif (ITIM), which is involved in modulation of cellular responses. 12 DCIR is expressed on the surface of most antigen-presenting cells (ie DCs, monocytes, macrophages, and B cells), as well as on granulocytes, and it is differentially expressed depending on the DC maturation status. 13 Lipopolysaccharide, IL-4, and TNF-␣ down-regulate DCIR expression on neutrophils. 14 The ITIM domain of DCIR contains the consensus sequence S/I/V/LxYxxI/V/L, including a tyrosine residue at position 7 (ie, ITYAEV). 13 Generally, when ITIM-containing receptors are engaged, they become tyrosine-phosphorylated and then transmit signals by binding and activating Src homology-2 domain (SH2)-containing tyrosine phosphatases (eg, SHP-1 and SHP-2) and/or the SH2-containing tyrosine inositol phosphate (SHIP). 15 In the case of DCIR, one study has demonstrated that, when phosphorylated, it recruits both SHP-1 and SHP-2. 16 Nevertheless, there is still no e...

Exosome release following activation of the dendritic cell immunoreceptor: A potential role in HIV-1 pathogenesis

“…4 supports the hypothesis that the inhibitor does not affect cellular metabolism of Raji-CD4-DCIR and Raji-CD4-DCIR-Y7F cells and DCIR inhibitor affect HIV-1 binding.) Raji-CD4-DCIR-Y7F cells have been previously described to limit HIV-1 infection in comparison with Raji-CD4-DCIR cells (Lambert et al, 2011) and result in Supplementary Fig. 5 validate that the inhibitor affect only the HIV-1 binding and attachment on Raji-CD4-DCIR.…”

“…4B). Since we already shown that inhibition of phosphatases SHP-1 and SHP-2, Src family tyrosine kinase, tyrosine kinase Syk, serine/threonine kinases PKC or MAP, significantly reduced HIV-1 binding and infection via DCIR (Lambert et al, 2011), we also pre-incubated cells with Src kinase inhibitor PP2 for 10 min before the 48 h contact with the anti-DCIR antibody. A decrease in exosome release was observed (Fig.…”

HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells

“…Recent reports, which show that HIV-1-infected lymphocytes are more potent inducers of IFN-␣ than HIV-1 particles and that HIV-1 binds to BDCA-2 and DCIR, suggest that, in addition to HCV, a similar mechanism of immune evasion may be used by HIV-1. 24,[34][35][36] In view of the central role of pDCs in regulating the immune system, our results provide insight into the role of HCV-pDC interaction in HCV immune evasion and are important for our understanding of the mechanisms leading to the establishment of chronic HCV infection. …”

Dendritic Cell Immunoreceptor Regulates Chikungunya Virus Pathogenesis in Mice

“…DCIR contains an inhibitory ITIM motif, and once engaged, DCIR undergoes tyrosine phosphorylation by Src kinases, leading to recruitment and activation of protein tyrosine phosphatases SHP-1 and SHP-2 and the dephosphorylation of substrates which prevent cellular activation (68,69). While the host pathways which are responsible for the induction of CHIKV-induced inflammatory disease are currently not known, DCIR has been shown to inhibit specific subsets of Toll-like receptors (53,54) and is thought to be paired with an activating CLR (DCAR) (70).…”