Targeting human langerin promotes HIV-1 specific humoral immune responses

Abstract

The main avenue for the development of an HIV-1 vaccine remains the induction of protective antibodies. A rationale approach is to target antigen to specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting of skin Langerhans cells (LC) with anti-Langerin mAbs fused with HIV-1 Gag antigen drives antigen-specific humoral responses. The development of these immunization strategies in humans requires a better understanding of early immune events driven by human LC. We therefore produced anti-Langerin mAbs fused with the HIV-1 gp140z Envelope (αLC.Env). First, we show that primary skin human LC and in vitro differentiated LC induce differentiation and expansion of naïve CD4+ T cells into T follicular helper (Tfh) cells. Second, when human LC are pre-treated with αLC.Env, differentiated Tfh cells significantly promote the production of specific IgG by B cells. Strikingly, HIV-Env-specific Ig are secreted by HIV-specific memory B cells. Consistently, we found that receptors and cytokines involved in Tfh differentiation and B cell functions are upregulated by LC during their maturation and after targeting Langerin. Finally, we show that subcutaneous immunization of mice by αLC.Env induces germinal center (GC) reaction in draining lymph nodes with higher numbers of Tfh cells, Env-specific B cells, as well as specific IgG serum levels compared to mice immunized with the non-targeting Env antigen. Altogether, we provide evidence that human LC properly targeted may be licensed to efficiently induce Tfh cell and B cell responses in GC.

Secondary Sites of the C‐type Lectin‐Like Fold

“…[22,23,153] Example 2: Langerin Langerin is a trimeric CLR expressed in Langerhans cells, where it plays a crucial role in the recognition and uptake of viral, fungal, and bacterial pathogens. [184][185][186][187] The CTLD of langerin harbors a single Ca 2 + -binding site with an EPN motif for Ca 2 + -coordination, implying specific recognition for mannose, glucose, and fucose through their equatorial hydroxy groups (Figure 6a). While murine and human langerin (Figure 6b) share a similar affinity for monosaccharides, the extended canonical CBS provides homolog-specific affinity and specificity for While the biphenyl moiety of the biphenyl mannoside interacts with a previously identified secondary site centered by residue M270 (shown in blue), the mannose moiety predominantly binds to the canonical CBS of DC-SIGN (shown in green).…”

Glycomimetics for the inhibition and modulation of lectins

“…152,704 The utility of langerin-based delivery has been explored previously using antibodies and has revealed that langerin mediated cargo uptake leads to crosspresentation of exogenous antigens, important for anti-viral and anti-cancer therapeutics. [705][706][707][708][709][710] In this respect, the recent development of the carbohydrate-based glycomimetic 189 for human langerin was reported. 711 The N-tosylated glucosamine 189 makes use of the Ca 2+ -mediated canonical hydroxy group coordination of the 3-and 4-OH groups.…”

STxB as an Antigen Delivery Tool for Mucosal Vaccination

“…On the contrary, CD8α negative DCs and Langerhans cells preferentially induce humoral responses [ 56 ]. Targeting DC2 via DCIR2 in mice [ 56 , 57 ] and Langerhans cells via langerin was more effective in activating follicular helper T cells and a humoral response than targeting DC1 [ 58 , 59 ].…”