Mycobacterium bovis BCG‐infected neutrophils and dendritic cells cooperate to induce specific T cell responses in humans and mice

Abstract

Neutrophils are increasingly thought to modulate dendritic cell (DC) functions. We investigated the role of the neutrophil-DC partnership in the response to Mycobacterium bovis BCG-the vaccine used against tuberculosis. We compared neutrophil-DC crosstalk in humans and mice, searching for functional differences. In both species, neutrophils captured fluorescent BCG-enhanced green fluorescent protein (EGFP) and were more phagocytic than DC. Non-apoptotic BCG-infected neutrophils clustered with immature DC, establishing intimate contacts with dendrites, at which fluorescent intact bacilli were observed. Physical interactions between neutrophils and DC were required for DC activation. Human BCG-infected DC produced interleukin (IL)-10, an inhibitory cytokine, whereas DC exposed to BCG-infected neutrophils produced low to undetectable amounts of the cytokine. Mouse BCG-infected neutrophils induced sustained IL-2 production by DC. Human DC exposed to BCG-infected neutrophils stimulated recall T cell reactivity from vaccinated donors. Mouse DC infected with recombinant ovalbumin (OVA)-producing BCG (rBCG ova ) elicited proliferation of TCR-OVA-transgenic CD4 and CD8 T cells. Moreover, exposing DC to rBCG ova -infected neutrophils enhanced OVA presentation. Thus, in mice and humans, neutrophils help DC to cross-present BCG antigens to T cells. Our results suggest that this "mØnage à trois" involving neutrophils, DC and T cells plays a major role in the immune response to BCG.

Mycobacterium bovis Bacillus Calmette-Guérin Vaccination Mobilizes Innate Myeloid-Derived Suppressor Cells Restraining In Vivo T Cell Priming via IL-1R–Dependent Nitric Oxide Production

“…3A). Mouse neutrophils produce TNF in response to BCG infection (13). Similar levels of intracellular TNF staining were observed for neutrophils and CD11b + Ly-6C int Ly-6G 2 cells after BCG infection (Fig.…”

“…Notably, understanding inflammatory/innate response to the tuberculosis vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) might give some clues as to why BCG does not consistently protect adults against pulmonary disease (11). We showed that during BCG vaccination in mouse models, neutrophils shuttle BCG from the skin to the draining lymph node (12) and establish cross-talk with DCs to facilitate the presentation of Ag to T cells (13).…”

Mycobacteria-Infected Dendritic Cells Attract Neutrophils That Produce IL-10 and Specifically Shut Down Th17 CD4 T Cells through Their IL-10 Receptor

“…Neutrophils are acute inflammatory cells that respond to mycobacterial infection. They engulf bacilli efficiently, both in vitro and in vivo (12,13). They also play a key role in granuloma formation through the secretion of CXCR3 ligands that recruit CD4 T cells (21).…”

“…Neutrophils are highly efficient phagocytic cells (12) and also play an important role during mycobacterial infection. In an intradermal BCG vaccination model in the mouse, we demonstrated that neutrophils recruited to the injection site could transfer live bacilli to the draining lymph node (13).…”

“…In an intradermal BCG vaccination model in the mouse, we demonstrated that neutrophils recruited to the injection site could transfer live bacilli to the draining lymph node (13). Infected neutrophils promote DC maturation and Ag presentation to T cells resulting in polarization toward the Th1 phenotype (12). This interaction involves the CD11b (aM) integrin that, together with CD18 (b2), forms CR3 (Mac-1) and is strongly expressed in neutrophils (14,15).…”