Secretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and-independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGFβ-activating integrin αvβ8 by cDC1. In contrast, αvβ8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets.

No abstract

Initiation of adaptive immunity to particulate antigens in lymph nodes largely depends on their presentation by migratory dendritic cells (DCs). DC subsets differ in their capacity to induce specific types of immunity, allowing subset-specific DC-targeting to influence vaccination and therapy outcomes. Faithful drug design, however, requires exact understanding of subset-specific versus global activation mechanisms. cDC1, the subset of DCs that excel in supporting immunity toward viruses, intracellular bacteria, and tumors, express uniquely high levels of the pattern recognition receptor TLR3. Using various murine genetic models, we show here that both, the cDC1 and cDC2 subsets of cDCs are activated and migrate equally well in response to TLR3 stimulation in a cell extrinsic and TNF-α dependent manner, but that cDC1 show a unique requirement for type I interferon signaling. Our findings reveal common and differing pathways regulating DC subset migration, offering important insights for the design of DC-based vaccination and therapy approaches.

Initiation of adaptive immunity to particulate antigens in lymph nodes largely depends on their presentation by migratory dendritic cells (DCs). DC subsets differ in their capacity to induce specific types of immunity, allowing subset-specific DC-targeting to influence vaccination and therapy outcomes. Faithful drug design however requires exact understanding of subset-specific versus global activation mechanisms. cDC1, the subset of DCs that excel in supporting immunity towards viruses, intracellular bacteria and tumors, express uniquely high levels of the pattern recognition receptor TLR3. Using various genetic models, we show here that both the cDC1 and cDC2 subsets of cDCs are activated and migrate equally well in response to TLR3 stimulation in a cell extrinsic and TNFα dependent manner, but that cDC1 show a unique requirement for type I interferon signaling. Our findings reveal common and differing pathways regulating DC subset migration, offering important insights for the design of DC-based vaccination and therapy approaches.

Rotavirus (RV) infection induces strong adaptive immunity. While protection from reinfection requires humoral immunity, initial clearance of infection depends on cytotoxic CD8 T cells. Type I classical dendritic cells (cDC1) excel at CD8 T cell induction through cross-presentation and are essential for optimal cytotoxicity towards RV. Upon sensing of infection-induced innate immune signals through pattern recognition receptors (PRRs), cumulating in autocrine type I interferon (IFN) signaling, cDC1 mature and migrate to the draining lymph nodes (LNs), where they prime adaptive immune cells. To analyze which PRR pathways lead to robust cytotoxicity in the context of RV infection, we measured RV-specific CD8 T cell priming in mice deficient for Toll-like receptor 3 (TLR3), recognizing double-stranded RNA, or for MyD88, the adapter for all other TLRs and IL-1 family cytokines. Individual TLR3- and MyD88-mediated signaling was not required for the priming of CD8 T cell responses to RV and neither deficiency impacted on RV clearance. Surprisingly, the accumulation of RV-specific CD8 T cells was also not altered in the absence of type I IFN signaling, while their ability to produce IFNγ and granzyme were blunted. Together, this suggests a substantial level of redundancy in the sensing of RV infection and the translation of signals into protective CD8 T cell immunity.