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Intravesical administration of BCG was the first immunotherapy approved by the FDA and it is still nowadays the treatment of choice for a subset of non-muscle invasive bladder cancer patients. Considering this precedent and the strong capabilities of BCG to trigger cellular responses, we hypothesized that systemic administration of BCG by the intravenous route (IV BCG), a vaccination strategy that has been found well-tolerated, highly immunogenic and effective at preventing tuberculosis infection in non-human primates, could result effective against lung tumors. Our data revealed that IV BCG, administered in a therapeutic scenario, slowed tumor growth and extended mouse survival in models of B16-F10 lung metastasis and in an orthotopic LLC lung cancer model, by enhancing both antitumoral innate and adaptive immune responses. IV BCG administration induced tumor-specific CD8+ T cell responses with enhanced cytotoxic function, in a process dependent on conventional type 1 Dendritic Cells (cDC1s). In addition, we found that BCG strongly activated both human and mouse NK cells. Remarkably, NK cell depletion prevented BCG-induced cDC1 recruitment to the tumor-bearing lung and reduced cDC1 upload with tumor-derived antigens, as well as the subsequent induction of tumor-specific CD8+ T cell responses and tumor control. Of note, IV BCG strongly synergized with the immune checkpoint inhibitor (ICI) anti-PD-L1 in lung tumors which were otherwise resistant to immune checkpoint blockade given as monotherapy, suggesting the IV BCG could represent a promising ICI-resensitizing cancer immunotherapy.

Summary MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Here, we find that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long-term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provides protection against systemic candidiasis in wild-type and Rag1-deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogates the protection conferred by MV130 against influenza A virus respiratory infection. MV130 induces reprogramming of both mouse bone marrow progenitor cells and in vitro human monocytes, promoting an enhanced cytokine production that relies on a metabolic shift. Our results unveil that the mucosal administration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity., Graphical abstract, Highlights • MV130 reduces morbi-mortality in mouse models of viral respiratory infection • MV130 modulates mouse immunity complying with key features of trained immunity • MV130 promotes reprogramming of mouse bone marrow progenitors • MV130 induces trained immunity in human monocytes, Brandi et al. investigate the mechanism of action of an inactivated polybacterial mucosal immunomodulator, MV130, which confers protection in patients suffering from recurrent respiratory infections. They show that MV130 induces trained immunity both in mouse bone marrow progenitors, resulting in protection from viral infection, and in human monocytes in vitro.

The Coronavirus Disease of 2019 (COVID-19) pandemic caused by SARS-CoV-2 led the Spanish government to impose a national lockdown in an attempt to control the spread of the infection. Mobility restrictions and the requirement of a medical prescription for serological testing for COVID-19 were included among the control measures. Under this scenario, between April 15th and June 15th, 2020, we performed an observational study including 449 individuals allowed to be tested according to the governmental restrictions, i.e. fulfilling the following prescription requirements: manifestation of COVID-19-compatible symptoms, contact with a confirmed COVID-19 patient, or employment as an essential worker, including health care workers, firefighters and public safety personnel such as police. Importantly, a relevant feature of the studied cohort was that none of the participants had been hospitalized. We analyzed SARS-CoV-2 IgG seropositivity in this specific cohort, uncovering intrinsic features of great demographic interest. The overall rate of IgG seropositivity was 33.69% (95% CI: 29.27–38.21). This frequency was comparable among the different participant occupations. A RT-PCR positive test, contact with a household member previously tested positive and the presence of COVID-19-compatible symptoms were positively associated with IgG + results. Among these symptoms, ageusia/anosmia was positively and independently associated with SARS-CoV-2 IgG seropositivity, while odynophagia was inversely associated. However, fever, ageusia/anosmia and asthenia were the most frequent symptoms described by IgG + subjects. Therefore, our data illustrate how specific cohorts display particular characteristics that should be taken into account when studying population-wide SARS-CoV-2 seroprevalence and key defining symptoms of COVID-19.

Sensing tissue damage is an ancient function of immune cells that is central to the regulation of inflammation, tissue repair, and immunity. In this issue of Immunity, Lai et al. (2020) uncover a role for the C-type lectin receptor Clec2d as a sensor of cell death, which directly detects histones released during necrosis and thus contributes to inflammation and immunopathology. C.d.F. is supported by the AECC Foundation (INVES192DELF). Work in the DS laboratory is funded by the CNIC; the European Research Council (ERC 2016 Consolidator Grant 725091); the European Commission (635122-PROCROP H2020); Ministerio de Ciencia, Innovacion e Universidades (MICINN), Agencia Estatal de Investigacion, and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R); Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); FIS-Instituto de Salud Carlos III, MICINN, and FEDER (RD16/0015/0018-REEM); the Acteria Foundation; Atresmedia (Constantes y Vitales prize); and Fundacio La Marato de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

Intravesical BCG is the gold-standard therapy for non-muscle invasive bladder cancer (NMIBC); however, it still fails in a significant proportion of patients, so improved treatment options are urgently needed. Here, we compared BCG antitumoral efficacy with another live attenuated mycobacteria, MTBVAC, in an orthotopic mouse model of bladder cancer (BC). We aimed to identify both bacterial and host immunological factors to understand the antitumoral mechanisms behind effective bacterial immunotherapy for BC. We found that the expression of the BCG-absent proteins ESAT6/CFP10 by MTBVAC was determinant in mediating bladder colonization by the bacteria, which correlated with augmented antitumoral efficacy. We further analyzed the mechanism of action of bacterial immunotherapy and found that it critically relied on the adaptive cytotoxic response. MTBVAC enhanced both tumor antigen-specific CD4+ and CD8+ T-cell responses, in a process dependent on stimulation of type 1 conventional dendritic cells. Importantly, improved intravesical bacterial immunotherapy using MBTVAC induced eradication of fully established bladder tumors, both as a monotherapy and specially in combination with the immune checkpoint inhibitor antiprogrammed cell death ligand 1 (anti PD-L1). These results contribute to the understanding of the mechanisms behind successful bacterial immunotherapy against BC and characterize a novel therapeutic approach for BCG-unresponsive NMIBC cases. This study was supported by Spanish Science and Innovation Ministry (RETOS COLABORACIÓN RTC-2017-6379-1 and RETOS INVESTIGACIÓN RTI2018- 097625-B-I00); and 'Gobierno de Aragón-Fondo Europeo de Desarrollo Regional (FEDER) 2014-2020: Construyendo Europa Desde Aragón'. The funders had no role in study design, data collection and analysis, and decision to publish or preparation of the manuscript. Sí

The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of 23 December 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols., Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, are urgently needed. We developed two COVID-19 vaccines based on modified vaccinia virus Ankara (MVA) vectors expressing the entire SARS-CoV-2 spike (S) protein (MVA-CoV2-S); their immunogenicity was evaluated in mice using DNA/MVA or MVA/MVA prime/boost immunizations. Both vaccines induced robust, broad, and polyfunctional S-specific CD4+ (mainly Th1) and CD8+ T-cell responses, with a T effector memory phenotype. DNA/MVA immunizations elicited higher T-cell responses. All vaccine regimens triggered high titers of IgG antibodies specific for the S, as well as for the receptor-binding domain; the predominance of the IgG2c isotype was indicative of Th1 immunity. Notably, serum samples from vaccinated mice neutralized SARS-CoV-2 in cell cultures, and those from MVA/MVA immunizations showed a higher neutralizing capacity. Remarkably, one or two doses of MVA-CoV2-S protect humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2. In addition, two doses of MVA-CoV2-S confer full inhibition of virus replication in the lungs. These results demonstrate the robust immunogenicity and full efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic. IMPORTANCE The continuous dissemination of the novel emerging SARS-CoV-2 virus, with more than 78 million infected cases worldwide and higher than 1,700,000 deaths as of 23 December 2020, highlights the urgent need for the development of novel vaccines against COVID-19. With this aim, we have developed novel vaccine candidates based on the poxvirus modified vaccinia virus Ankara (MVA) strain expressing the full-length SARS-CoV-2 spike (S) protein, and we have evaluated their immunogenicity in mice using DNA/MVA or MVA/MVA prime/boost immunization protocols. The results showed the induction of a potent S-specific T-cell response and high titers of neutralizing antibodies. Remarkably, humanized K18-hACE2 mice immunized with one or two doses of the MVA-based vaccine were 100% protected from SARS-CoV-2 lethality. Moreover, two doses of the vaccine prevented virus replication in lungs. Our findings prove the robust immunogenicity and efficacy of MVA-based COVID-19 vaccines in animal models and support its translation to the clinic.

Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.

Highlights • Tissue damage recognition by myeloid cells shapes immune responses. • Recognition of immunogenic cell death by myeloid cells promotes inflammation. • Myeloid sensing of tissue damage may also dampen further injury by immunopathology., Myeloid cells are components of the innate immune system that represent the first line of defense. Tissue damage, associated with pathological conditions such as infection, cancer or autoimmunity, leads to the exposure of the intracellular content to the extracellular environment. Myeloid cells detect ligands exposed or released by dead cells through specific receptors that signal for a diversity of responses. Inflammatory responses triggered by myeloid cells after sensing tissue injury can contribute to resolution of the damage. The signaling response following dead-cell sensing by myeloid cells can contribute either to an inflammatory or a regulatory response. We review herein some representative examples of how myeloid cells react to the recognition of cell death during specific tissue damage contexts. A deep understanding of the cellular and molecular mechanisms underlying these processes would allow to improve therapeutical interventions in pathologies associated with tissue damage.

COVID-19 pandemic caused by SARS-CoV-2 led the Spanish government to impose a national lockdown in an attempt to control the spread of the infection. Mobility restrictions but also the requirement of a medical prescription to gain access to serological testing for COVID-19 were included among the measures. Under this scenario, between April 15th to June 15th, 2020, we performed a seroprevalence observational study including 449 individuals that fulfill prescription requirements: manifesting COVID-19 compatible symptoms, being in contact with a COVID-19 confirmed case or belonging to essential occupations including healthcare workers, firefighters or public safety personnel such as police. Importantly, none of the participants was hospitalized. Altogether, we studied this specific, non-commonly addressed cohort for SARS-CoV-2 seroprevalence, uncovering intrinsic features of great demographic interest. The overall rate of IgG seropositivity was 33.69% (95% CI: 29.27 – 38.21). This seroprevalence was comparable between different occupations performed by the participants. However, contacts with confirmed cases associated positively with IgG+ results, with stronger correlation if being a household member. The number of symptoms also correlated positively with IgG+ prevalence. Ageusia/anosmia, pneumonia and cutaneous manifestations were the top-three symptoms that most strongly associated with IgG+ seroprevalence. However, while pneumonia and cutaneous manifestations were barely present in our cohort, fever, ageusia/anosmia and asthenia were the most frequently symptoms described within IgG+ subjects. Therefore, our data illustrate how specific cohorts display heterogeneous characteristics that should be taken into account when identifying population seroprevalence against SARS-CoV-2 and key defining symptoms for COVID-19.

The ‘cancer cell fusion’ theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis., Research in the laboratory of EL-C was supported by “Fundación para la Investigación Biomédica La Paz Hospital” ((FIBHULP) and “Fundación Familia Alonso”.

Sepsis is a global health priority. Despite thorough studies in mice models, its molecular and cellular basis remain unclear and there is no pharmacological effective treatment other than antimicrobial and supportive therapy. During sepsis, T cells exhaustion compromises patients’ outcome, and immune checkpoints (ICs) become crucial players in disease management. Here, a total of 425 patients with systemic inflammatory response criteria and 127 controls were studied. Soluble SIGLEC5 (sSIGLEC5) levels in plasma were higher in patients with sepsis compared to the other groups and even higher in those patients with septic-shock. sSIGLEC5 plasma levels were higher in non-survivors than in survivors and ROC curves analysis revealed sSIGLEC5 as a survival marker (cut-off ≤ 523.6 ng/mL). In vitro experiments illustrated how SIGLEC5 impaired CD8+ proliferation through binding to PSGL1. Blocking the SIGLEC5/PSGL1 axis reverted the latter effect. Mechanistically, SIGLEC5 overexpression was driven by HIF1α. Exogenous sSIGLEC5 accelerated death and magnified acute lung injury in mice models. Our data demonstrates how plasma sSIGLEC5 level on admission predicts death and stratifies patients with sepsis. This molecule exhibits the hallmarks of an IC ligand.

After both sterile and infectious insults, damage is inflicted on tissues leading to accidental or programmed cell death. In addition, events of programmed cell death also take place under homeostatic conditions, such as in embryo development or in the turnover of hematopoietic cells. Mammalian tissues are seeded with myeloid immune cells, which harbor a plethora of receptors that allow the detection of cell death, modulating immune responses. The myeloid C-type lectin receptors (CLRs) are one of the most prominent families of receptors involved in tailoring immunity after sensing dead cells. In this chapter, we will cover a diversity of signals arising from different forms of cell death and how they are recognized by myeloid CLRs. We will also explore how myeloid cells develop their sentinel function, exploring how some of these CLRs identify cell death and the type of responses triggered thereof. In particular, we will focus on DNGR-1 (CLEC9A), Mincle (CLEC4E), CLL-1 (CLEC12A), LOX-1 (OLR1), CD301 (CLEC10A) and DEC-205 (LY75) as paradigmatic death-sensing CLRs expressed by myeloid cells. The molecular processes triggered after cell death recognition by myeloid CLRs contribute to the regulation of immune responses in pathologies associated with tissue damage, such as infection, autoimmunity and cancer. A better understanding of these processes may help to improve the current approaches for therapeutic intervention.

Simple Summary Amongst colorectal cancers, there is significant heterogeneity, which hinders the search for a single disease detection approach. Clinical prognostic markers are urgently needed. The aim of our prospective study was to analyse the possible role of pre-operative soluble SIGLEC5 plasma levels in patient prognosis and evolution. In a cohort of 114 patients with colorectal cancer, our data confirmed the relevance of soluble SIGLEC5 levels as a prognosis marker and exitus predictor. Altogether, our data indicate that levels of this protein could be a novel and promising biomarker for patients with colorectal cancer. Abstract Colorectal cancer (CRC) is the second most deadly and third most commonly diagnosed cancer worldwide. There is significant heterogeneity among patients with CRC, which hinders the search for a standard approach for the detection of this disease. Therefore, the identification of robust prognostic markers for patients with CRC represents an urgent clinical need. In search of such biomarkers, a total of 114 patients with colorectal cancer and 67 healthy participants were studied. Soluble SIGLEC5 (sSIGLEC5) levels were higher in plasma from patients with CRC compared with healthy volunteers. Additionally, sSIGLEC5 levels were higher in exitus than in survivors, and the receiver operating characteristic curve analysis revealed sSIGLEC5 to be an exitus predictor (area under the curve 0.853; cut-off > 412.6 ng/mL) in these patients. A Kaplan–Meier analysis showed that patients with high levels of sSIGLEC5 had significantly shorter overall survival (hazard ratio 15.68; 95% CI 4.571–53.81; p ≤ 0.0001) than those with lower sSIGLEC5 levels. Our study suggests that sSIGLEC5 is a soluble prognosis marker and exitus predictor in CRC.

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection. Neutrophils display circadian oscillations in numbers and phenotype in the circulation. Adrover and colleagues now identify the molecular regulators of neutrophil aging and show that genetic disruption of this process has major consequences in immune cell trafficking, anti-microbial defense, and vascular health., This study was supported by Intramural grants from A∗STAR to L.G.N., BES-2013-065550 to J.M.A., BES-2010-032828 to M.C.-A, and JCI-2012-14147 to L.A.W (all from Ministerio de Economía, Industria y Competitividad; MEIC). Additional MEIC grants were SAF2014-61993-EXP to C.L.-R.; SAF2015-68632-R to M.A.M. and SAF-2013-42920R and SAF2016-79040Rto D.S. D.S. also received 635122-PROCROP H2020 from the European Commission and ERC CoG 725091 from the European Research Council (ERC). ERC AdG 692511 PROVASC from the ERC and SFB1123-A1 from the Deutsche Forschungsgemeinschaft were given to C.W.; MHA VD1.2/81Z1600212 from the German Center for Cardiovascular Research (DZHK) was given to C.W. and O.S.; SFB1123-A6 was given to O.S.; SFB914-B08 was given to O.S. and C.W.; and INST 211/604-2, ZA 428/12-1, and ZA 428/13-1 were given to A.Z. This study was also supported by PI12/00494 from Fondo de Investigaciones Sanitarias (FIS) to C.M.; PI13/01979, Cardiovascular Network grant RD 12/0042/0054, and CIBERCV to B.I.; SAF2015-65607-R, SAF2013-49662-EXP, and PCIN-2014-103 from MEIC; and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) to A.H. The CNIC is supported by the MEIC and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).

Type-I conventional dendritic cells (cDC1s) are key in inducing adaptive immunity. Using single-cell sequencing, Ginhoux and colleagues (Immunity 2019;50:1069-1083.e8) find that a subset of activated cDC1s in bacteria-infected skin is critical for neutrophil recruitment via the production of VEGF-α. These results reveal a crucial function for cDC1s beyond antigen presentation. C.d.F. is supported by AECC Foundation as recipient of an ‘Ayuda Fundación Científica AECC a personal investigador en cancer’. Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), Agencia Estatal de Investigación and FEDER (European Fund for Regional Development); B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MINECO and FEDER; Foundation Acteria; Constantes y Vitales prize (Atresmedia); Foundation La Marató de TV3 (201723); the European Commission (635122-PROCROP H2020) and the European Research Council (ERCConsolidator Grant 725091). The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Sí

Despite the crucial role of tissue-resident memory T (Trm) cells in protective immunity, their priming remains poorly understood. Here, we have shown differential priming requirements for Trm versus circulating memory CD8+ T cells. In vaccinia cutaneous-infected mice, DNGR-1-mediated crosspresentation was required for optimal Trm cell priming but not for their skin differentiation or for circulating memory T cell generation. DNGR-1+ dendritic cells (DCs) promoted T-bet transcription-factor induction and retention of CD8+ T cells in the lymph nodes (LNs). Inhibition of LN egress enhanced Trm cell generation, whereas genetic or antibody blockade of DNGR-1 or specific signals provided during priming by DNGR-1+ DCs, such as interleukin-12 (IL-12), IL-15, or CD24, impaired Trm cell priming. DNGR-1 also regulated Trm cell generation during influenza infection. Moreover, protective immunity depended on optimal Trm cell induction by DNGR-1+ DCs. Our results reveal specific priming requirements for CD8+ Trm cells during viral infection and vaccination.

Candida glabrata is the second most common pathogen of severe candidiasis in immunocompromised hosts, following C. albicans. Although C. glabrata and C. albicans belong to the same genus, they are phylogenetically distinct. C-type lectin receptors (CLRs), acting as pattern-recognition receptors (PRRs), play critical roles in host defense against C. albicans infections. However, our understanding of the specific roles of CLRs in host defense against C. glabrata is limited. Here, we explored the potential roles of the C-type lectins Dectin-1 and Dectin-2 in host defense against C. glabrata. We found that both Dectin-1-deficient mice (Dectin-1−/−) and Dectin-2-deficient mice (Dectin-2−/−) are more susceptible to C. glabrata infection. Dectin-1confers host higher sensitivity for sensing C. glabrata infections, while the effect of Dectin-2 in the host defense against C. glabrata is infection dose dependent. Dectin-1 is required for host myeloid cells recognition, killing of C. glabrata, and development of subsequent Th1 and Th17 cell-mediated adaptive immune response. Significantly impaired inflammatory responses such as inflammatory cells recruitment and cytokines release that were induced by C. glabrata were manifested in Dectin-1-deficient mice. Together, our study demonstrates that Dectin-1 plays an important role in host defense against systemic Candida glabrata infections, indicating a previous unknown control mechanism for this particular type of infection in host. Our study, therefore, provides new insights into the host defense against C. glabrata.

Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the gene Clec9a, which senses tissue damage and favors cross-presentation of dead-cell material to CD8+ T cells. Here we find that DNGR-1 additionally reduces host-damaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic Candida albicans infection without affecting fungal burden. This effect is B and T cell–independent and attributable to increased neutrophilia in DNGR-1–deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by Cxcl2) production by cDC1s during Candida infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR-1–mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology., C.d.F. is supported by the AECC Foundation as the recipient of an “Ayuda Fundación Científica AECC a personal investigador en cancer.” P.S.-L. is funded by grant BES-2015-072699 from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU). M.E. is the recipient of a CNIC International Ph.D. Programme fellowship “la Caixa”-Severo Ochoa OSLC-CNIC-2013-04. S.K.W. is supported by a European Molecular Biology Organization (EMBO) Long-Term Fellowship (grant ALTF 438-2016) and a CNIC-International Postdoctoral Programme Fellowship (grant 17230-2016). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, Agencia Estatal de Investigación, and Fondos Europeos de Desarrollo Regional (FEDER); B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MICINN, and FEDER; Acteria Foundation; Constantes y Vitales prize (Atresmedia); La Marató de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020); and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently—in an autocrine manner—induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1–independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2−/−, and to a lesser extent Dectin-1−/− mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced., Author summary T helper 2 (Th2) responses, which are initiated by dendritic cells (DCs), can cause allergic diseases, but they can also provide protection against metabolic disorders and parasitic helminth infections. As such, there is great interest in better understanding how their activity is induced and regulated by DCs. Parasitic helminths can potently induce Th2 responses. However, how helminths condition DCs for priming of Th2 responses remains incompletely understood. Here, we find that egg antigens from the parasitic helminth Schistosoma mansoni bind to pattern-recognition receptors (PRRs) Dectin-1 and Dectin-2 on DCs. This binding triggers a signaling cascade in DCs that results in synthesis of eicosanoid prostaglandin E2 (PGE2). PGE2 is sensed by the DCs themselves, resulting in expression of OX40 ligand (OX40L), which subsequently enables the DCs to promote Th2 differentiation. We show that this pathway is activated independently of omega-1 (ω-1), which is a glycoprotein secreted by the eggs and previously shown to condition DCs for priming of Th2 responses. Moreover, we demonstrate that this ω-1–independent pathway is crucial for Th2 induction and egg-driven immunopathology following S. mansoni infection in vivo. In summary, we identified a novel pathway in DCs involving Dectin-1/2–induced autocrine PGE2 signaling through which Th2 responses are induced.

Myeloid C-type lectin receptors (CLRs) are important sensors of self and non-self that work in concert with other pattern recognition receptors (PRRs). CLRs have been previously classified based on their signaling motifs as activating or inhibitory receptors. However, specific features of the ligand binding process may result in distinct signaling through a single motif, resulting in the triggering of non-canonical pathways. In addition, CLR ligands are frequently exposed in complex structures that simultaneously bind different CLRs and other PRRs, which lead to integration of heterologous signaling among diverse receptors. Herein, we will review how sensing by myeloid CLRs and crosstalk with heterologous receptors is modulated by many factors affecting their signaling and resulting in differential outcomes for immunity and inflammation. Finding common features among those flexible responses initiated by diverse CLR-ligand partners will help to harness CLR function in immunity and inflammation. CF is supported by AECC Foundation as recipient of an ``Ayuda Fundacion Cientifica AECC a personal investigador en cancer.´´ SI is funded by grant SAF2015-74561-JIN from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Fund for Regional Development (FEDER). PS-L is funded by grant BES-2015-072699 (´´Ayudas para contratos predoctorales para la formacion de doctores 2015´´) from MINECO. MM-L received a FPU fellowship (AP2010-5935) from the Spanish Ministry of Education. Work in the DS laboratory is funded by the CNIC and grant SAF2016-79040-R from MINECO and FEDER; B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MINECO, and FEDER; Foundation Acteria; Constantes y Vitales prize (Atresmedia); Foundation La Marato de TV3 (201723); the European Commission (635122-PROCROP H2020); and the European Research Council (ERC-Consolidator Grant 725091). The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The authors have no conflicting financial interests. Sí

Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans., This work was supported by grants from the MINECO [SAF2013‐45331‐R and SAF2016‐79792‐R (AEI/FEDER, UE)] to AC and JJS‐E, La Marató TV3 Foundation (20133431) to AC and (SAF2014‐52009‐R) to SA. ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organization for Scientific Research to MGN, and Wellcome Trust, the Medical Research Council (MRC; UK), the MRC Centre for Medical Mycology at the University of Aberdeen to GDB. DAB and AE receive MINECO FPI fellowships, AR a MINECO Juan de la Cierva award and JD‐A a La Caixa Foundation PhD fellowship.

Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources. his work was supported by funds from the British Heart Foundation (FS/14/3/30518 to T.G. and S.N.), the People Programme (Marie Curie Actions) of the EU’s 7th Framework Programme (FP7/2007-2013) under REA grant agreement 608765 (to T.G. and S.N.), and by the Wellcome Trust (098291/Z/12/Z to S.N.). D.S. is supported by the CNIC, SAF2016-79040-R from the Spanish Ministerio de Ciencia, and ERC-2016-CoG 725091 from the European Research Council. M.T. and A.R. are supported by the Sinergia grant CRSII3_160719 of the Swiss National Science Foundation. G.G. is supported by the Wellcome Trust and the MRC. U.H.v.A. and A.T. are supported by the Ragon Institute of MGH, MIT and Harvard and the HMS Center for Immune Imaging. Sí

Summary β-Glucan-induced trained immunity in myeloid cells leads to long-term protection against secondary infections. Although previous studies have characterized this phenomenon, strategies to boost trained immunity remain undefined. We found that β-glucan-trained macrophages from mice with a myeloid-specific deletion of the phosphatase SHIP-1 (LysMΔSHIP-1) showed enhanced proinflammatory cytokine production in response to lipopolysaccharide. Following β-glucan training, SHIP-1-deficient macrophages exhibited increased phosphorylation of Akt and mTOR targets, correlating with augmented glycolytic metabolism. Enhanced training in the absence of SHIP-1 relied on histone methylation and acetylation. Trained LysMΔSHIP-1 mice produced increased amounts of proinflammatory cytokines upon rechallenge in vivo and were better protected against Candida albicans infection compared with control littermates. Pharmacological inhibition of SHIP-1 enhanced trained immunity against Candida infection in mouse macrophages and human peripheral blood mononuclear cells. Our data establish proof of concept for improvement of trained immunity and a strategy to achieve it by targeting SHIP-1., Graphical Abstract, Highlights • β-glucan-induced trained immunity is enhanced by SHIP-1 deletion in macrophages • SHIP-1 regulates molecular, metabolic, and epigenetic hallmarks of trained immunity • Myeloid SHIP-1 deficiency improves protection conferred by trained immunity • SHIP-1 pharmacological inhibition enhances trained immunity in mice and human cells, Trained immunity leads to long-term protection, but strategies to boost it require further investigation. Saz-Leal et al. show that myeloid SHIP-1 deletion enhances trained immunity, improving the response to pathogen-specific or heterologous challenges. Pharmacological inhibition of SHIP-1 also potentiates this phenomenon, thereby revealing a potential tool to harness trained immunity.

In this issue of Immunity, Warnatsch et al. (2017) describe how neutrophils measure their microbial opponents by differential shuttling of reactive oxygen species (ROS), a process that determines their recruitment and distribution and ultimately the strength of anti-microbial responses. Sí