Targeting human langerin promotes HIV-1 specific humoral immune responses

• DOI: 10.1371/journal.ppat.1009749
• Publication Date: 2021-07-29T18:48:45Z
• Authors: Jérôme Kervevan; Aurélie Bouteau; Juliane S. Lanza; Adele Hammoudi; Sandra Zurawski; Mathieu Surenaud; Lydie Dieudonné; Marion Bonnet; Cécile Lefebvre; Hakim Hocini; Romain Marlin; Aurélie Guguin; Barbara Hersant; Oana Hermeziu; Elisabeth Menu; Christine Lacabaratz; Jean-Daniel Lelièvre; Gerard Zurawski; Véronique Godot; Sandrine Henri; Botond Z. Igyártó; Yves Levy; Sylvain Cardinaud
• Keywords: 0301 basic medicine; 570; QH301-705.5; [SDV]Life Sciences [q-bio]; Medical Immunology; Mouse models; Q1; Lymphocyte Activation; Antibodies; T helper cells; Mice; 03 medical and health sciences; Antigens, CD; Cell differentiation; Animals; Humans; Lectins, C-Type; Biology (General); human langerin; AIDS Vaccines; Department of Microbiology and Immunology; B cells; HIV vaccines; env Gene Products, Human Immunodeficiency Virus; RC581-607; Immunity, Humoral; 3. Good health; Mannose-Binding Lectins; Thomas Jefferson University; Medical Microbiology; Langerhans Cells; HIV-1; Cytokines; Immunologic diseases. Allergy; humoral immune; Research Article

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.