RESUMO
Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.
Assuntos
Neuroimunomodulação , Humanos , Animais , Intestinos/imunologia , Homeostase , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Neurônios/metabolismo , Neurônios/imunologia , Neuropeptídeos/metabolismo , Sistema Nervoso Entérico/imunologia , Sistema Nervoso Entérico/metabolismoRESUMO
Among antibodies, IgA is unique because it has evolved to be secreted onto mucosal surfaces. The structure of IgA and the associated secretory component allow IgA to survive the highly proteolytic environment of mucosal surfaces but also substantially limit IgA's ability to activate effector functions on immune cells. Despite these characteristics, IgA is critical for both preventing enteric infections and shaping the local microbiome. IgA's function is determined by a distinct antigen-binding repertoire, composed of antibodies with a variety of specificities, from permissive polyspecificity to cross-reactivity to exquisite specificity to a single epitope, which act together to regulate intestinal bacteria. Development of the unique function and specificities of IgA is shaped by local cues provided by the gut-associated lymphoid tissue, driven by the constantly changing environment of the intestine and microbiota.
Assuntos
Imunidade nas Mucosas , Imunoglobulina A , Animais , Humanos , Mucosa Intestinal , Nódulos Linfáticos AgregadosRESUMO
The interplay between the immune and nervous systems has been acknowledged in the past, but only more recent studies have started to unravel the cellular and molecular players of such interactions. Mounting evidence indicates that environmental signals are sensed by discrete neuro-immune cell units (NICUs), which represent defined anatomical locations in which immune and neuronal cells colocalize and functionally interact to steer tissue physiology and protection. These units have now been described in multiple tissues throughout the body, including lymphoid organs, adipose tissue, and mucosal barriers. As such, NICUs are emerging as important orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, inflammation, tissue repair, and thermogenesis. In this review we focus on the impact of NICUs in tissue physiology and how this fast-evolving field is driving a paradigm shift in our understanding of immunoregulation and organismal physiology.
Assuntos
Sistema Imunitário , Sistema Nervoso , Neuroimunomodulação , Animais , Humanos , Imunidade nas Mucosas , ImunomodulaçãoRESUMO
The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.
Assuntos
Tecido Adiposo/imunologia , Colo/imunologia , Mucosa/imunologia , Músculo Esquelético/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Especificidade de ÓrgãosRESUMO
Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.
Assuntos
Tosse/fisiopatologia , Glicolipídeos/metabolismo , Nociceptores/fisiologia , Fatores de Virulência/metabolismo , Adulto , Animais , Linhagem Celular , Tosse/etiologia , Tosse/microbiologia , Feminino , Glicolipídeos/fisiologia , Cobaias , Interações Hospedeiro-Patógeno , Humanos , Lipídeos/fisiologia , Pulmão/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Tuberculose/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/fisiopatologia , Fatores de Virulência/fisiologiaRESUMO
Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.
Assuntos
Imunidade nas Mucosas/imunologia , Interleucina-18/imunologia , Mucosa Intestinal/imunologia , Animais , Citocinas/imunologia , Sistema Nervoso Entérico/imunologia , Sistema Nervoso Entérico/metabolismo , Células Epiteliais/imunologia , Feminino , Células Caliciformes/imunologia , Interleucina-18/biossíntese , Mucosa Intestinal/metabolismo , Intestino Delgado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Ratos , Ratos Sprague-Dawley , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Transdução de Sinais/imunologiaRESUMO
Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.
Assuntos
Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Nociceptores/fisiologia , Animais , Epitélio/metabolismo , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/microbiologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/metabolismo , Nódulos Linfáticos Agregados/inervação , Nódulos Linfáticos Agregados/metabolismo , Infecções por Salmonella/metabolismo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologiaRESUMO
The intestinal epithelium is a highly structured tissue composed of repeating crypt-villus units. Enterocytes perform the diverse tasks of absorbing a wide range of nutrients while protecting the body from the harsh bacterium-rich environment. It is unknown whether these tasks are spatially zonated along the villus axis. Here, we extracted a large panel of landmark genes characterized by transcriptomics of laser capture microdissected villus segments and utilized it for single-cell spatial reconstruction, uncovering broad zonation of enterocyte function along the villus. We found that enterocytes at villus bottoms express an anti-bacterial gene program in a microbiome-dependent manner. They next shift to sequential expression of carbohydrates, peptides, and fat absorption machineries in distinct villus compartments. Finally, they induce a Cd73 immune-modulatory program at the villus tips. Our approach can be used to uncover zonation patterns in other organs when prior knowledge of landmark genes is lacking.
Assuntos
Enterócitos/metabolismo , Transcriptoma , Animais , Diferenciação Celular , Movimento Celular , Enterócitos/citologia , Enterócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Célula ÚnicaRESUMO
Commensal microbes induce cytokine-producing effector tissue-resident CD4+ T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here, we report that commensal-specific intestinal Th17 cells possess an anti-inflammatory phenotype marked by expression of interleukin (IL)-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific Th17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific Th17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor Th17 cell population. Th17 cells acquired IL-10 expression and anti-inflammatory phenotype in the small-intestinal lamina propria. IL-10 production by CD4+ T cells and IL-10 signaling in intestinal macrophages drove IL-10 expression by commensal-specific Th17 cells. Intestinal commensal-specific Th17 cells possessed immunoregulatory functions and curbed effector T cell activity in vitro and in vivo in an IL-10-dependent and c-MAF-dependent manner. Our results suggest that tissue-resident commensal-specific Th17 cells perform regulatory functions in mucosal homeostasis.
Assuntos
Microbioma Gastrointestinal , Células Th17 , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Anti-InflamatóriosRESUMO
Lymph nodes (LNs) are critical sites for shaping tissue-specific adaptive immunity. However, the impact of LN sharing between multiple organs on such tailoring is less understood. Here, we describe the drainage hierarchy of the pancreas, liver, and the upper small intestine (duodenum) into three murine LNs. Migratory dendritic cells (migDCs), key in instructing adaptive immune outcome, exhibited stronger pro-inflammatory signatures when originating from the pancreas or liver than from the duodenum. Qualitatively different migDC mixing in each shared LN influenced pancreatic ß-cell-reactive T cells to acquire gut-homing and tolerogenic phenotypes proportional to duodenal co-drainage. However, duodenal viral infections rendered non-intestinal migDCs and ß-cell-reactive T cells more pro-inflammatory in all shared LNs, resulting in elevated pancreatic islet lymphocyte infiltration. Our study uncovers immune crosstalk through LN co-drainage as a powerful force regulating pancreatic autoimmunity.
Assuntos
Autoimunidade , Pâncreas , Camundongos , Animais , Pâncreas/patologia , Fígado , Linfócitos T , LinfonodosRESUMO
Pathogenic enteric viruses are a major cause of morbidity and mortality, particularly among children in developing countries. The host response to enteric viruses occurs primarily within the mucosa, where the intestinal immune system must balance protection against pathogens with tissue protection and tolerance to harmless commensal bacteria and food. Here, we summarize current knowledge in natural immunity to enteric viruses, highlighting specialized features of the intestinal immune system. We further discuss how knowledge of intestinal anti-viral mechanisms can be translated into vaccine development with particular focus on immunization in the oral route. Research reveals that the intestine is a complex interface between enteric viruses and the host where environmental factors influence susceptibility and immunity to infection, while viral infections can have lasting implications for host health. A deeper mechanistic understanding of enteric anti-viral immunity with this broader context can ultimately lead to better vaccines for existing and emerging viruses.
Assuntos
Infecções por Enterovirus , Vacinas , Vírus , Antígenos Virais , Criança , Humanos , Imunidade Inata , Mucosa Intestinal , IntestinosRESUMO
While blood antibodies mediate protective immunity in most organs, whether they protect nasal surfaces in the upper airway is unclear. Using multiple viral infection models in mice, we found that blood-borne antibodies could not defend the olfactory epithelium. Despite high serum antibody titers, pathogens infected nasal turbinates, and neurotropic microbes invaded the brain. Using passive antibody transfers and parabiosis, we identified a restrictive blood-endothelial barrier that excluded circulating antibodies from the olfactory mucosa. Plasma cell depletions demonstrated that plasma cells must reside within olfactory tissue to achieve sterilizing immunity. Antibody blockade and genetically deficient models revealed that this local immunity required CD4+ T cells and CXCR3. Many vaccine adjuvants failed to generate olfactory plasma cells, but mucosal immunizations established humoral protection of the olfactory surface. Our identification of a blood-olfactory barrier and the requirement for tissue-derived antibody has implications for vaccinology, respiratory and CNS pathogen transmission, and B cell fate decisions.
Assuntos
Linfócitos B , Plasmócitos , Animais , Camundongos , Linfócitos T , Imunoglobulinas , Encéfalo , Imunidade nas Mucosas , Anticorpos AntiviraisRESUMO
Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed a systematic approach to predict HLA class-II-specific epitopes using the humanized bacteria-originated T cell antigen (hBOTA) algorithm. We identified a diverse set of microbiome epitopes spanning all major taxa that are compatible with presentation by multiple HLA-II alleles. In particular, we uncovered an immunodominant epitope from the TonB-dependent receptor SusC that was universally recognized and ubiquitous among Bacteroidales. In healthy human subjects, SusC-reactive T cell responses were characterized by IL-10-dominant cytokine profiles, whereas in patients with active Crohn's disease, responses were associated with elevated IL-17A. Our results highlight the potential of targeted antigen discovery within the microbiome to reveal principles of tolerance and functional transitions during inflammation.
Assuntos
Doença de Crohn , Epitopos Imunodominantes , Linfócitos T CD4-Positivos , Epitopos de Linfócito T , Humanos , Interleucina-10 , Interleucina-17RESUMO
Interactions between the nervous and immune systems were recognized long ago, but recent studies show that this crosstalk occurs more frequently than was previously appreciated. Moreover, technological advances have enabled the identification of the molecular mediators and receptors that enable the interaction between these two complex systems and provide new insights on the role of neuroimmune crosstalk in organismal physiology. Most neuroimmune interactions occur at discrete anatomical locations in which neurons and immune cells colocalize. Here, we describe the interactions of the different branches of the peripheral nervous system with immune cells in various organs, including the skin, intestine, lung, and adipose tissue. We highlight how neuroimmune crosstalk orchestrates physiological processes such as host defense, tissue repair, metabolism, and thermogenesis. Unraveling these intricate relationships is invaluable to explore the therapeutic potential of neuroimmune interactions.
Assuntos
Sistema Imunitário , Neuroimunomodulação , Neuroimunomodulação/fisiologia , Sistema Nervoso PeriféricoRESUMO
The key sites within the gastrointestinal (GI) tract where T cells mediate effector responses and the impact of these responses on intestinal stem cells (ISCs) remain unclear. Using experimental bone marrow transplantation to model immune-mediated GI damage and 3D imaging to analyze T cell localization, we found that the ISC compartment is the primary intestinal site targeted by T cells after transplantation. Recruitment to the crypt base region resulted in direct T cell engagement with the stem cell compartment and loss of crypt base columnar ISCs, which expressed both MHC classes I and II. Vasculature expressing the adhesion molecule MAdCAM-1 clustered near the crypt base, preferentially regulating crypt compartment invasion and ISC reduction without affecting T cell migration to villi. These findings indicate that allogeneic T cells rapidly access the stem cell niche after transplantation, and this targeted recruitment to the stem cell compartment results in ISC loss during immune-mediated GI damage.
Assuntos
Células-Tronco Adultas/imunologia , Transplante de Medula Óssea , Mucosa Intestinal/imunologia , Nicho de Células-Tronco/imunologia , Linfócitos T/imunologia , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Moléculas de Adesão Celular/metabolismo , Movimento Celular , Citotoxicidade Imunológica , Feminino , Humanos , Imageamento Tridimensional , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Modelos Animais , Mucoproteínas , Transplante HomólogoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease (ILD) that affects lung mechanical functions and gas exchange. IPF is caused by increased fibroblast activity and collagen deposition that compromise the alveolar-capillary barrier. Identifying an effective therapy for IPF remains a clinical challenge. Chemokines are key proteins in cell communication that have functions in immunity as well as in tissue homeostasis, damage, and repair. Chemokine receptor signaling induces the activation and proliferation of lung-resident cells, including alveolar macrophages (AMs) and fibroblasts. AMs are an important source of chemokines and cytokines during IPF. We highlight the complexity of this system and, based on insights from genetic and transcriptomic studies, propose a new role for homeostatic chemokine imbalance in IPF, with implications for putative therapeutic targets.
Assuntos
Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Quimiocinas/metabolismo , Macrófagos Alveolares , Citocinas/metabolismo , Transdução de Sinais , PulmãoRESUMO
Mast cells are important for eradication of intestinal nematodes; however, their precise mechanisms of action have remained elusive, especially in the early phase of infection. We found that Spi-B-deficient mice had increased numbers of mast cells and rapidly expelled the Heligmosomoides polygyrus (Hp) nematode. This was accompanied by induction of interleukin-13 (IL-13)-producing group 2 innate lymphoid cells (ILC2) and goblet cell hyperplasia. Immediately after Hp infection, mast cells were rapidly activated to produce IL-33 in response to ATP released from apoptotic intestinal epithelial cells. In vivo inhibition of the P2X7 ATP receptor rendered the Spi-B-deficient mice susceptible to Hp, concomitant with elimination of mast cell activation and IL-13-producing ILC2 induction. These results uncover a previously unknown role for mast cells in innate immunity in that activation of mast cells by ATP orchestrates the development of a protective type 2 immune response, in part by producing IL-33, which contributes to ILC2 activation.
Assuntos
Helmintíase/imunologia , Helmintíase/parasitologia , Helmintos/imunologia , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Mastócitos/imunologia , Trifosfato de Adenosina/metabolismo , Animais , Comunicação Celular , Diferenciação Celular , Modelos Animais de Doenças , Resistência à Doença/genética , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Expressão Gênica , Helmintíase/genética , Imunofenotipagem , Interleucina-33/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Mucosa Intestinal/patologia , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.
Assuntos
Colo do Útero/microbiologia , Infecções por HIV/microbiologia , Vagina/microbiologia , Animais , Bactérias Anaeróbias , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Lactobacillus , Camundongos , Microbiota/imunologia , Prevotella , África do SulRESUMO
Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier.
Assuntos
Gengiva/imunologia , Imunidade nas Mucosas/imunologia , Vigilância Imunológica/imunologia , Mucosa Bucal/imunologia , Células Th17/imunologia , Animais , Citometria de Fluxo , Gengiva/microbiologia , Humanos , Mastigação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota , Mucosa Bucal/microbiologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-ß. Paralyzed DCs secreted TGF-ß and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen-presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis- and trauma-induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention.