Human Plasmacytoid Dendritic Cells Efficiently Capture HIV-1 Envelope Glycoproteins via CD4 for Antigen Presentation

Abstract

Advances in HIV-1 vaccine clinical trials and preclinical research indicate that the virus envelope glycoproteins (Env) are likely to be an essential component of a prophylactic vaccine. Efficient antigen uptake and presentation by dendritic cells (DCs) is important for strong CD4+ T helper cell responses and the development of effective humoral immune responses. Here, we examined the capacity of distinct primary human DC subsets to internalise and present recombinant Env to CD4+ T cells. Consistent with their specific receptor expression, skin DCs bound and internalised Env via C-type lectin receptors (CLRs) while blood DC subsets, including CD1c+ myeloid DCs (MDCs), CD123+ plasmacytoid DCs (PDCs) and CD141+ DCs exhibited a restricted repertoire of CLRs and relied on CD4 for uptake of Env. Despite a generally poor capacity for antigen uptake compared to MDCs, the high expression of CD4 on PDCs allowed them to bind and internalise Env very efficiently. CD4-mediated uptake delivered Env to EEA1+ endosomes that progressed to Lamp1+ and MHC class II+ lysosomes where internalised Env was degraded rapidly. Finally, all three blood DC subsets were able to internalise an Env-CMV pp65 fusion protein via CD4 and stimulate pp65-specific CD4+ T cells. Thus, in the in vitro systems described here, CD4-mediated uptake of Env is a functional pathway leading to antigen presentation and this may therefore be a mechanism utilised by blood DCs, including PDCs, for generating immune responses to Env-based vaccines.

Neutrophils acquire the capacity for antigen presentation to memory CD4+ T cells in vitro and ex vivo

“…[37][38][39] We used this method to assess whether neutrophils are capable of presenting antigens to T cells in a side-by-side comparison with monocyte and DC subsets. Flow cytometry-sorted neutrophils and monocyte and DC subsets were incubated with pp65 and cocultured with CFSE-labeled autologous CD4 1 T cells for 5 days.…”

Broadly Neutralizing Antibody VRC01 Prevents HIV-1 Transmission from Plasmacytoid Dendritic Cells to CD4 T Lymphocytes

“…Plasmacytoid dendritic cells (pDC) link innate and adaptive immunity and produce various cytokines and chemokines, especially type I interferons (IFN) (14)(15)(16). In addition, pDC present antigens and stimulate adaptive immune response as antigen-presenting cells, although with less efficiency than myeloid dendritic cells (mDC) (17)(18)(19). pDC were susceptible to HIV-1 infection (20, 21) with low levels of viral replication due to expression of various host restriction factors, such as SAMHD1 (22,23).…”

Dendritic Cell Interactions with HIV-1 Envelope Glycoprotein: Implications for Preventing Transmission

“…Blood DCs express a more restricted CLR repertoire including DCIR, DEC-205, and BDCA-2 (the latter on PDCs only) and tend to rely on CD4 for Env binding. In the context of soluble Env protein alone, this is a functional pathway for internalization and antigen presentation (Sandgren et al 2013). HIV also exploits non-glycan dependent binding to other DC-expressed pattern recognition receptors, including siglec-1 and syndecan-3, for capture and transfer to CD4 + T cells (Tsegaye and Pohlmann 2010).…”

“…In relation to HIV binding, LCs uniquely express high levels of langerin. The various dermal DCs express combinations of dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), mannose receptor (MR), dendritic cell immunoreceptor (DCIR), and DEC-205 (Harman et al 2013a;Sandgren et al 2013). The expression patterns of CLRs on lamina propria DCs are currently less well defined.…”

“…In the case of Env, its high glycosylation naturally targets it to DCs via certain CLRs, including DC-SIGN. Additionally, in blood DCs, including PDCs, that display restricted CLR repertoires, the high-affinity interaction between Env and CD4 also enables efficient uptake and presentation of Env to CD4 + T cells (Sandgren et al 2013). Another receptor that appears attractive for antigen targeting is CD40.…”