Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node

Abstract

Mucosal immunity is poorly activated after systemic immunization with protein Ags. Nevertheless, induction of mucosal immunity in such a manner would be an attractive and simple way to overcome the intrinsic difficulties in delivering Ag to such sites. Flagellin from Salmonella enterica serovar Typhimurium (FliC) can impact markedly on host immunity, in part via its recognition by TLR5. In this study, we show that systemic immunization with soluble FliC (sFliC) drives distinct immune responses concurrently in the mesenteric lymph nodes (MLN) and the spleen after i.p. and s.c. immunization. In the MLN, but not the spleen, sFliC drives a TLR5-dependent recruitment of CD103+ dendritic cells (DCs), which correlates with a diminution in CD103+ DC numbers in the lamina propria. In the MLN, CD103+ DCs carry Ag and are the major primers of endogenous and transgenic T cell priming. A key consequence of these interactions with CD103+ DCs in the MLN is an increase in local regulatory T cell differentiation. In parallel, systemic sFliC immunization results in a pronounced switching of FliC-specific B cells to IgA in the MLN but not elsewhere. Loss of TLR5 has more impact on MLN than splenic Ab responses, reflected in an ablation of IgA, but not IgG, serum Ab titers. Therefore, systemic sFliC immunization targets CD103+ DCs and drives distinct mucosal T and B cell responses. This offers a potential “Trojan horse” approach to modulate mucosal immunity by systemically immunizing with sFliC.

Commensal microbiota drive proliferation of conventional and Foxp3+Regulatory CD4+T cells in mesenteric lymph nodes and Peyer's patches

“…Although our data are supported by a recent report on a protective role for TLR5 defi ciency for colitis development in a T cell transfer model [54], another study reported, in contrast, a potentiating effect of the TLR5 agonist fl agellin on induction, expansion and suppressive activity of Foxp3 + Tregs [28,52]. While differing compositions of commensal enteric communities between laboratories might explain these contrasting results, our data clearly show that microbiota-driven proliferation of conventional CD4 + T cells and Foxp3 + Tregs can occur in the absence of TLR-signaling.…”

Different populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon

“…It is well established that TLR activation can lead to DC migration in the intestine, which has been shown for R848 (ref. 55), a TLR7/8 agonist, and soluble flagellin356, which activates TLR5. DCs do not require MyD88-mediated TLR signalling to induce Th2 responses against S. mansoni eggs57, but the effects of S. mansoni eggs on DC migration have not previously been addressed.…”

B1b Cells Recognize Protective Antigens after Natural Infection and Vaccination

“…The dendritic cell subset involved in Tfh priming, Ig switching, and other T effector functions may not always be the same since different subsets can provide these functions in different sites concurrently. For instance, we have found that after flagellin immunization CD103 + dendritic cells prime for IgA and IgG in the mesenteric lymph node but not the spleen, and that after Salmonella infection monocyte-derived dendritic cells help prime for IFNγ-expression in T-cells but not IgG2a responses (70, 71). In parallel, B-cells that have engaged antigen interact with primed Tfh cells also within the T-zone.…”