Abstract
Primary T-cell activation at mucosal sites is of utmost importance for the development of vaccination strategies. T-cell priming after vaginal immunization, with ovalbumin and CpG oligodeoxynucleotide adjuvant as model vaccine formulation, was studied in vivo in hormone-synchronized mice and compared to the one induced by the nasal route. Twenty-four hours after both vaginal or nasal immunization, antigen-loaded dendritic cells were detected within the respective draining lymph nodes. Vaginal immunization elicited a strong recruitment of antigen-specific CD4+ T cells into draining lymph nodes that was more rapid than the one observed following nasal immunization. T-cell clonal expansion was first detected in iliac lymph nodes, draining the genital tract, and proliferated T cells disseminated towards distal lymph nodes and spleen similarly to what observed following nasal immunization. T cells were indeed activated by the antigen encounter and acquired homing molecules essential to disseminate towards distal lymphoid organs as confirmed by the modulation of CD45RB, CD69, CD44 and CD62L marker expression. A multi-type Galton Watson branching process, previously used for in vitro analysis of T-cell proliferation, was applied to model in vivo CFSE proliferation data in draining lymph nodes 57 hours following immunization, in order to calculate the probabilistic decision of a cell to enter in division, rest in quiescence or migrate/die. The modelling analysis indicated that the probability of a cell to proliferate was higher following vaginal than nasal immunization. All together these data show that vaginal immunization, despite the absence of an organized mucosal associated inductive site in the genital tract, is very efficient in priming antigen-specific CD4+ T cells and inducing their dissemination from draining lymph nodes towards distal lymphoid organs.
Highlights
T-cell priming at mucosal sites is of primary importance for the development of mucosal vaccine formulations and prime-boost strategies aimed to elicit mucosal and systemic effector immune responses
In distal lymph nodes and in the spleen, antigen-loaded dendritic cells (DCs) were not detected at any time point (Fig. 1 A and B), indicating that following vaginal immunization antigen presentation occurs within lymph nodes draining the immunization site, and not in other lymphoid sites, in accordance with what was observed and previously reported for nasal immunization [32]
In the present work antigen-specific CD4+ T-cell primary activation and dissemination following vaginal immunization was characterized and compared to the one elicited by the nasal route
Summary
T-cell priming at mucosal sites is of primary importance for the development of mucosal vaccine formulations and prime-boost strategies aimed to elicit mucosal and systemic effector immune responses. The induction of mucosal immune responses requires the presence of a mucosa-associated lymphoid tissue that provides a continuous source of B and T cells to mucosal effector sites [8]. Inductive sites for mucosal immunity consist of organized mucosaassociated lymphoid tissue as well as local and regional draining lymph nodes (LNs), whereas the effector sites include distinctly different histological compartments, mainly consisting of the lamina propria of various mucosae [9]. Inductive sites in the gastro-intestinal and respiratory tracts have been well defined and are composed by aggregated lymphoid tissues (gut-, nasal- and bronchial-associated lymphoid tissues respectively) and mucosaassociated lymph nodes (mesenteric and mediastinal lymph nodes), on the contrary the vaginal mucosa is devoid of histologically demonstrable organised mucosa-associated lymphoid tissue and the role of inductive site is played directly by draining iliac lymph nodes [5]
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