CD103+CD11b+ mucosal classical dendritic cells initiate long-term switched antibody responses to flagellin

Abstract

Antibody responses induced at mucosal and nonmucosal sites demonstrate a significant level of autonomy. Here, we demonstrate a key role for mucosal interferon regulatory factor-4 (IRF4)-dependent CD103 þ CD11b þ (DP), classical dendritic cells (cDCs) in the induction of T-dependent immunoglobulin G (IgG) and immunoglobulin A (IgA) responses in the mesenteric lymph node (MLN) following systemic immunization with soluble flagellin (sFliC). In contrast, IRF8-dependent CD103 þ CD11b À (SP) are not required for these responses. The lack of this response correlated with a complete absence of sFliC-specific plasma cells in the MLN, small intestinal lamina propria, and surprisingly also the bone marrow (BM). Many sFliC-specific plasma cells accumulating in the BM of immunized wild-type mice expressed a 4 b 7 þ , suggesting a mucosal origin. Collectively, these results suggest that mucosal DP cDC contribute to the generation of the sFliC-specific plasma cell pool in the BM and thus serve as a bridge linking the mucosal and systemic immune system.

Intestinal CD103+CD11b+ cDC2 Conventional Dendritic Cells Are Required for Primary CD4+ T and B Cell Responses to Soluble Flagellin

“…Intraperitoneal immunization of sFliC induces a rapid MyD88-dependent accumulation of intestinal-derived CD103 + cDC2 in the MLN ( 1 , 3 ). To analyse the role of TLR5 in this response, WT and TLR5 −/− mice were immunized with sFliC and the cDC response analyzed by flow cytometry and in situ by immunofluorescence 24 h post-immunization.…”

“…We have previously shown that sFliC can drive a long-term mucosal adaptive response after i.p. immunization ( 1 , 3 ). Furthermore, we also have shown that s.c. and i.p.…”

“…One antigen that can induce both mucosal and systemic immunity concurrently after intraperitoneal (i.p.) or s.c. immunization is purified, soluble flagellin (sFliC) from Salmonella Typhimurium ( 1 – 3 ). This 51 kDa bacterial motility protein is the only known ligand for TLR5 ( 4 ).…”

“…Moreover, using Cd11c-cre.Irf4 fl / fl mice, which have diminished numbers of CD103 + CD11b + cDCs in the small intestine lamina propria and a 90% reduction of this population in the MLN, we showed that this subset was essential for the induction of adaptive immune responses in the MLN, while splenic cDC2 play only a partial role. For clarity, CD103 + CD11b + cDCs will be referred to throughout as CD103 + cDC2 ( 3 ). This indicates that i.p., immunization with sFliC can bridge both systemic and mucosal immune systems through the targeting of a single mucosal cDC subset.…”

Migration of intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation

“…Our data showing that the migration and upregulation of costimulatory molecules by DCs in response to TLR stimuli in vivo can result from trans-activation of DCs therefore suggest that differences in migration capacities may not be linked to the polarization of T cell responses. However it is important to note that not all TLR ligands can induce migration in trans, as signaling through TLR5, that is only expressed on cDC2, does not induce cDC1 migration in vivo (Flores-Langarica et al, 2017). Taken together, these findings indicate that TLR based adjuvants and targeting need to be examined individually for their impact on specific DC subsets if their effects on the immune system are to be understood in depth.…”