RESUMO
Breastfeeding offers demonstrable benefits to newborns and infants by providing nourishment and immune protection and by shaping the gut commensal microbiota. Although it has been appreciated for decades that breast milk contains complement components, the physiological relevance of complement in breast milk remains undefined. Here, we demonstrate that weanling mice fostered by complement-deficient dams rapidly succumb when exposed to murine pathogen Citrobacter rodentium (CR), whereas pups fostered on complement-containing milk from wild-type dams can tolerate CR challenge. The complement components in breast milk were shown to directly lyse specific members of gram-positive gut commensal microbiota via a C1-dependent, antibody-independent mechanism, resulting in the deposition of the membrane attack complex and subsequent bacterial lysis. By selectively eliminating members of the commensal gut community, complement components from breast milk shape neonate and infant gut microbial composition to be protective against environmental pathogens such as CR.
Assuntos
Proteínas do Sistema Complemento , Microbioma Gastrointestinal , Leite , Animais , Feminino , Humanos , Lactente , Camundongos , Bactérias , Aleitamento Materno , Citrobacter rodentium , Proteínas do Sistema Complemento/análise , Fatores Imunológicos , Saúde do Lactente , Leite Humano , Leite/química , Infecções por Enterobacteriaceae/imunologiaRESUMO
Neonates are born with an immature immune system and rely on the transfer of immunity from their mothers. Maternal antibodies are transferred via the placenta and breast milk. Although the role of placentally transferred immunoglobulin G (IgG) is established, less is known about the selection of antibodies transferred via breast milk and the mechanisms by which they provide protection against neonatal disease. Evidence suggests that breast milk antibodies play multifaceted roles, preventing infection and supporting the selection of commensals and tolerizing immunity during infancy. Here, we discuss emerging data related to the importance of breast milk antibodies in neonatal immunity and development.
Assuntos
Anticorpos/metabolismo , Leite Humano/imunologia , Animais , Homeostase , Humanos , Imunidade , Fatores Imunológicos/farmacologia , MicrobiotaRESUMO
Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens.
Assuntos
Fatores Imunológicos/farmacologia , RNA/farmacologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Antígenos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Proteína DEAD-box 58/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Imunidade/efeitos dos fármacos , Imunocompetência , Memória Imunológica , Imunoterapia , Interferons/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Peptídeos/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Linfócitos T/efeitos dos fármacosRESUMO
Ticks transmit a diverse array of microbes to vertebrate hosts, including human pathogens, which has led to a human-centric focus in this vector system. Far less is known about pathogens of ticks themselves. Here, we discover that a toxin in blacklegged ticks (Ixodes scapularis) horizontally acquired from bacteria-called domesticated amidase effector 2 (dae2)-has evolved to kill mammalian skin microbes with remarkable efficiency. Secreted into the saliva and gut of ticks, Dae2 limits skin-associated staphylococci in ticks while feeding. In contrast, Dae2 has no intrinsic ability to kill Borrelia burgdorferi, the tick-borne Lyme disease bacterial pathogen. These findings suggest ticks resist their own pathogens while tolerating symbionts. Thus, just as tick symbionts can be pathogenic to humans, mammalian commensals can be harmful to ticks. Our study underscores how virulence is context-dependent and bolsters the idea that "pathogen" is a status and not an identity.
Assuntos
Bactérias/metabolismo , Fatores Imunológicos/metabolismo , Ixodes/fisiologia , Pele/microbiologia , Simbiose , Animais , Antibacterianos/farmacologia , Biocatálise , Parede Celular/metabolismo , Comportamento Alimentar , Feminino , Trato Gastrointestinal/metabolismo , Interações Hospedeiro-Patógeno , Camundongos , Modelos Moleculares , Peptidoglicano/metabolismo , Filogenia , Saliva/metabolismo , Glândulas Salivares/metabolismo , Staphylococcus epidermidis/fisiologia , Homologia Estrutural de Proteína , Especificidade por Substrato , Regulação para CimaRESUMO
The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it.
Assuntos
Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Metagenoma/fisiologia , Animais , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Doenças do Sistema Digestório/imunologia , Doenças do Sistema Digestório/microbiologia , Doenças do Sistema Digestório/terapia , Trato Gastrointestinal/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Metagenoma/efeitos dos fármacos , Probióticos/uso terapêuticoRESUMO
Fetal neurodevelopment in utero is profoundly shaped by both systemic maternal immunity and local processes at the maternal-fetal interface. Immune pathways are a critical participant in the normal physiology of pregnancy and perturbations of maternal immunity due to infections during this period have been increasingly linked to a diverse array of poor neurological outcomes, including diseases that manifest much later in postnatal life. While experimental models of maternal immune activation (MIA) have provided groundbreaking characterizations of the maternal pathways underlying pathogenesis, less commonly examined are the immune factors that serve pathogen-independent developmental functions in the embryo and fetus. In this review, we explore what is known about the in vivo role of immune factors in fetal neurodevelopment during normal pregnancy and provide an overview of how MIA perturbs the proper orchestration of this sequence of events. Finally, we discuss how the dysregulation of immune factors may contribute to the manifestation of a variety of neurological disorders.
Assuntos
Feto/embriologia , Feto/imunologia , Fatores Imunológicos/metabolismo , Sistema Nervoso/embriologia , Sistema Nervoso/imunologia , Animais , Citocinas/metabolismo , Feminino , Humanos , Troca Materno-Fetal/imunologia , Modelos Biológicos , GravidezRESUMO
Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.
Assuntos
Células Dendríticas/imunologia , Imunoterapia Adotiva , Proteínas de Membrana/imunologia , Neoplasias Experimentais/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Humanos , Fatores Imunológicos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologiaRESUMO
Interferon signaling mediates resistance to immune checkpoint blockade therapy, but the underlying mechanisms are poorly understood. In this issue of Immunity, Cucolo et al. identify RIPK1 as an interferon-stimulated gene with potent effects on cell extrinsic and intrinsic immunotherapy resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Neoplasias , Proteína Serina-Treonina Quinases de Interação com Receptores , Humanos , Fatores Imunológicos , InterferonsRESUMO
Immune-system maturation starts early in life, but studies investigating immune-system education in human infants remain scarce. In a recent issue of Cell, Henrick et al. study early gut microbiota and immune-system development in two infant cohorts. The authors describe that Bifidobacteria can use milk sugars to produce immunoregulatory compounds that induce immune tolerance and reduce intestinal inflammation.
Assuntos
Bifidobacterium/metabolismo , Sistema Imunitário/crescimento & desenvolvimento , Intestinos/imunologia , Intestinos/microbiologia , Leite Humano/química , Oligossacarídeos/metabolismo , Animais , Aleitamento Materno , Microbioma Gastrointestinal/fisiologia , Humanos , Tolerância Imunológica/imunologia , Fatores Imunológicos/química , Imunomodulação/imunologia , Lactente , Suécia , Estados UnidosRESUMO
Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1 that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 couples with inhibitory G protein (Gi), the major intracellular signaling effector for human chemokine receptors, and exhibits constitutive signaling activity; the ligand(s) for BILF1 are unknown. We studied the origins of BILF1's constitutive activity through structure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer. The 3.2-Å resolution cryo-electron microscopy structure revealed an extracellular loop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomous receptor activation. Rather, amino acid substitutions within BILF1 transmembrane regions at hallmark ligand-activated class A GPCR "microswitches" stabilized a constitutively active BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, the constitutive activity of BILF1 promotes immunosuppression and virulence independent of ligand availability, with implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Fatores Imunológicos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Proteínas Virais/imunologia , Animais , Sítios de Ligação/imunologia , Linhagem Celular , Quimiocinas/imunologia , Microscopia Crioeletrônica/métodos , Infecções por Vírus Epstein-Barr/virologia , Células HEK293 , Humanos , Ligação Proteica/imunologia , Células Sf9 , Transdução de Sinais/imunologiaRESUMO
In this issue of Immunity, Weulersse et al. and Braun et al. explain how CD226 expression loss on CD8+ T cells impairs TCR-driven activation, and thereby anti-tumor effector responses, tantamount to taking the CD8+ T cell's foot off the gas pedal.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Antígenos de Diferenciação de Linfócitos T , Humanos , Fatores Imunológicos , Imunoterapia , Neoplasias/terapiaRESUMO
Innate immune sensors that detect nucleic acids are attractive targets for therapeutic intervention because of their diverse roles in many disease processes. In detecting RNA and DNA from either self or non-self, nucleic acid sensors mediate the pathogenesis of many autoimmune and inflammatory conditions. Despite promising pre-clinical data and investigational use in the clinic, relatively few drugs targeting nucleic acid sensors are approved for therapeutic use. Nevertheless, there is growing appreciation for the untapped potential of nucleic acid sensors as therapeutic targets, driven by the need for better therapies for cancer, infectious diseases, and autoimmune disorders. This review highlights the diverse mechanisms by which nucleic acid sensors are activated and exert their biological effects in the context of various disease settings. We discuss current therapeutic strategies utilizing agonists and antagonists targeting nucleic acid sensors to treat infectious disease, cancer, and autoimmune and inflammatory disorders.
Assuntos
Autoantígenos/imunologia , Doenças Autoimunes/imunologia , DNA/imunologia , Imunidade Inata/imunologia , RNA/imunologia , Animais , Humanos , Fatores Imunológicos/farmacologia , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais/imunologiaRESUMO
The complex architecture of transmembrane proteins requires quality control (QC) of folding, membrane positioning, and trafficking as prerequisites for cellular homeostasis and intercellular communication. However, it has remained unclear whether transmembrane protein-specific QC hubs exist. Here we identify cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), as a co-chaperone that specifically determines chaperone activity of HSP90 toward transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with HSP90. Among the multiple transmembrane protein clients of CRBN-AHA1-HSP90 revealed by cell surface proteomics, we identify the amino acid transporter LAT1/CD98hc as a determinant of IMiD activity in multiple myeloma (MM) and present an Anticalin-based CD98hc radiopharmaceutical for MM radio-theranostics. These data establish the CRBN-AHA1-HSP90 axis in the biogenesis of transmembrane proteins, link IMiD activity to tumor metabolism, and nominate CD98hc and LAT1 as attractive diagnostic and therapeutic targets in MM.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Fatores Imunológicos/farmacologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Chaperonas Moleculares/metabolismo , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Células Tumorais CultivadasRESUMO
The growing field of immune metabolism has revealed promising indications for metabolic targets to modulate anti-cancer immunity. Combination therapies involving metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy, radiation, and/or diet now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment (TME). Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. These changes also reveal opportunities to reshape the TME by targeting metabolic pathways to favor immunity. Here we explore current strategies that shift immune cell metabolism to pro-inflammatory states in the TME and highlight a need to better replicate physiologic conditions to select targets, clarify mechanisms, and optimize metabolic inhibitors. Unifying our understanding of these pathways and interactions within the heterogenous TME will be instrumental to advance this promising field and enhance immunotherapy.
Assuntos
Imunoterapia/tendências , Neoplasias/metabolismo , Microambiente Tumoral/imunologia , Humanos , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacosRESUMO
First isolated in China in early 2020, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for the ongoing pandemic of Coronavirus Disease 2019 (COVID-19). The disease has been spreading rapidly across the globe, with the largest burden falling on China, Europe, and the United States. COVID-19 is a new clinical syndrome, characterized by respiratory symptoms with varying degrees of severity, from mild upper respiratory illness to severe interstitial pneumonia and acute respiratory distress syndrome, aggravated by thrombosis in the pulmonary microcirculation. Three main phases of disease progression have been proposed for COVID-19: an early infection phase, a pulmonary phase, and a hyperinflammation phase. Although current understanding of COVID-19 treatment is mainly derived from small uncontrolled trials that are affected by a number of biases, strong background noise, and a litany of confounding factors, emerging awareness suggests that drugs currently used to treat COVID-19 (antiviral drugs, antimalarial drugs, immunomodulators, anticoagulants, and antibodies) should be evaluated in relation to the pathophysiology of disease progression. Drawing upon the dramatic experiences taking place in Italy and around the world, here we review the changes in the evolution of the disease and focus on current treatment uncertainties and promising new therapies.
Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Saúde Global , Humanos , Fatores Imunológicos/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , SARS-CoV-2RESUMO
Wolman's disease, a severe form of lysosomal acid lipase deficiency, leads to pathologic lipid accumulation in the liver and gut that, without treatment, is fatal in infancy. Although continued enzyme-replacement therapy (ERT) in combination with dietary fat restriction prolongs life, its therapeutic effect may wane over time. Allogeneic hematopoietic stem-cell transplantation (HSCT) offers a more definitive solution but carries a high risk of death. Here we describe an infant with Wolman's disease who received high-dose ERT, together with dietary fat restriction and rituximab-based B-cell depletion, as a bridge to early HSCT. At 32 months, the infant was independent of ERT and disease-free, with 100% donor chimerism in the peripheral blood.
Assuntos
Gorduras na Dieta , Terapia de Reposição de Enzimas , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos , Rituximab , Doença de Wolman , Humanos , Lactente , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Quimerismo , Gorduras na Dieta/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Transplante Homólogo , Doença de Wolman/dietoterapia , Doença de Wolman/tratamento farmacológico , Doença de Wolman/imunologia , Doença de Wolman/terapiaRESUMO
The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.
Assuntos
Adenocarcinoma/terapia , Fatores Imunológicos/imunologia , Imunoterapia , Subpopulações de Linfócitos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Linfócitos T CD8-Positivos/imunologia , Epigenômica , Feminino , Perfilação da Expressão Gênica , Humanos , Fatores Imunológicos/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Cultura Primária de Células , Neoplasias PancreáticasRESUMO
Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.
Assuntos
Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , HumanosRESUMO
ABSTRACT: Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. This leads to the activation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4, VITT sera, and the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl.