Abstract
Mucosal nasal vaccine development, although ideal to protect from pathogens invading mucosally, is limited by the lack of specific adjuvant. We recently used P1, a conserved region of HIV-1 gp41-envelope glycoprotein, as efficient antigen in a prophylactic HIV-1 mucosal vaccine applied nasally. Herein, P1 immunomodulation properties were assessed on human nasal mucosal models by measuring induction of cytokine and chemokine production, intracellular signaling pathways, mucosal dendritic cell (DC) activation, and T cell proliferation. P1 adjuvant properties were evaluated by quantification of antigen-specific B cell responses against a model antigen in an in vitro immunization model. We now demonstrated that P1 has additional immunological properties. P1 initiates immune responses by inducing nasal epithelial cells to secrete the Th2-cytokine thymic stromal lymphopoietin (TSLP), a described mucosal adjuvant. Secreted TSLP activates, in turn, intracellular calcium flux and PAR-2-associated NFAT signaling pathway regulated by microRNA-4485. Thereafter, P1 induces mucosal dendritic cell maturation, secretion of TSLP in a TSLP-receptor (R)-dependent autocrine loop, but also IL-6, IL-10, IL-8, CCL20, CCL22, and MMP-9, and proliferation of CD4+ T cells. Finally, P1 acts as an adjuvant to stimulate antigen-specific B cell responses in vitro. Overall, P1 is a multi-functional domain with various immuno-modulatory properties. In addition to being a protective vaccine antigen for HIV prevention, P1 acts as adjuvant for other mucosal vaccines able to stimulate humoral and cellular antigen-specific responses.
Highlights
Most human pathogens initiate infection at mucosal sites, only a few licensed mucosal vaccines have been established so far [1]
The P1 sequence is relatively conserved, in contrast to highly mutated regions of HIV-1 envelope gp120, the P1 sequence varies between HIV-1 clade A that is common in West Africa, clade B that predominates in Europe and the USA, and clade C that predominates in Africa and China (Figure 1B)
P1 clade C differs from P1 clades B and A by the ELDKW motif, we have previously shown to be determinant in P1 clade B binding to galactosyl ceramide (GalCer), the epithelial HIV-1 receptor [9, 10]
Summary
Most human pathogens initiate infection at mucosal sites, only a few licensed mucosal vaccines have been established so far [1]. Intranasal immunization, by inducing an antigen-specific immunity in both the mucosal and systemic compartments and by being applied in a atraumatic manner following pulverization, is currently considered as an ideal strategy for prevention against pathogens invading mucosa [2,3,4]. Mucosal immunization is highly compartmentalized with unique pathways linking the inductive and effector sites [2, 3]. Very limited efforts have been made to understand the mechanisms by which nasal vaccines and dedicated adjuvants activate the local nasal innate and adaptive immunity as a first step to establish an effective vaccination
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