Abstract
Priming of T cells is a key event in vaccination, since it bears a decisive influence on the type and magnitude of the immune response. T-cell priming after mucosal immunization via the nasal route was studied by investigating the distribution of antigen-loaded antigen presenting cells (APCs) and primed antigen-specific T cells. Nasal immunization studies were conducted using the model protein antigen ovalbumin (OVA) plus CpG oligodeoxynucleotide adjuvant. Trafficking of antigen-specific primed T cells was analyzed in vivo after adoptive transfer of OVA-specific transgenic T cells in the presence or absence of fingolimod, a drug that causes lymphocytes sequestration within lymph nodes. Antigen-loaded APCs were observed in mediastinal lymph nodes, draining the respiratory tract, but not in distal lymph nodes. Antigen-specific proliferating T cells were first observed within draining lymph nodes, and later in distal iliac and mesenteric lymph nodes and in the spleen. The presence at distal sites was due to migration of locally primed T cells as shown by fingolimod treatment that caused a drastic reduction of proliferated T cells in non-draining lymph nodes and an accumulation of extensively divided T cells within draining lymph nodes. Homing of nasally primed T cells in distal iliac lymph nodes was CD62L-dependent, while entry into mesenteric lymph nodes depended on both CD62L and α4β7, as shown by in vivo antibody-mediated inhibition of T-cell trafficking. These data, elucidating the trafficking of antigen-specific primed T cells to non-draining peripheral and mucosa-associated lymph nodes following nasal immunization, provide relevant insights for the design of vaccination strategies based on mucosal priming.
Highlights
Mucosal T-cell priming is a critical early event that deeply influences the type and magnitude of the immune response to local vaccination
To study the fate of Ag-bearing antigen presenting cells (APCs) after mucosal administration, OVA-Alexa fluor 647 conjugate was inoculated with the mucosal adjuvant CpG ODN by the nasal route, and the presence of Agloaded Dendritic cells (DCs) and B cells was studied at different time points, in both draining and distal lymph nodes and spleen
In this work we show that T cells - and not antigen-loaded APCs - primed by the nasal route with OVA and CpG ODN migrate to distal lymph nodes and to the spleen, and that the entry of nasally primed T cells into iliac lymph nodes is strictly CD62L-dependent, while homing to mesenteric lymph nodes is regulated by both CD62L and a4b7
Summary
Mucosal T-cell priming is a critical early event that deeply influences the type and magnitude of the immune response to local vaccination. Mucosal inductive sites are constituted by organized mucosa-associated lymphoid tissues (MALT) as well as local mucosa-draining lymph nodes, where antigens (Ag) are taken up, and B- and T-cell responses are induced [1]. Tcell priming influences both B- and T-cell memory generation, determining the success of a vaccination strategy [3,4]. The study of mucosal immune responses has been mainly focused on the characterization of effector humoral responses [8,9,10], and only recently mucosal T-cell priming is beginning to be elucidated [11,12,13,14]
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