Control of adaptive immunity by the innate immune system

Iwasaki, Akiko; Medzhitov, Ruslan

doi:10.1038/ni.3123

Cited by 2,160Immune Response and InflammationImmunotherapy and Immune ResponsesImmune responses and vaccinations

Control of adaptive immunity by the innate immune system

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Iwasaki, Akiko, Medzhitov, Ruslan·2015·Nature Immunology

DOI 10.1038/ni.3123PMC PMC4507498

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Abstract

Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity.

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TLRs do not directly initiate phagocytosis but facilitate it more effectively.
“TLRs do not directly initiate phagocytosis but facilitate it more effectively [27].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [27]
In “Recognition in different compartments” (page not provided), the paper says that activation of PRRs including TLRs leads to enhanced phagocytosis. It does not state that TLRs cannot directly initiate phagocytosis, so that part of the claim is not supported by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In over 400 healthy middle to early old age participants from the Whitehall II Cohort study, self-reported short sleep duration in men, but not in women, was related to shorter leukocyte telomere length.
“In more than 400 healthy, middle to early old age participants drawn from the Whitehall II Cohort study, self-reported short sleep duration in men, but not in women, was related to shorter leukocyte telomere length”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [267]

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CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells
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Detection of prokaryotic mRNA signifies microbial viability and promotes immunity
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Allergic host defences
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“When CD22 is engaged by its sialic acid ligand, it activates the lipid phosphatase SHIP, which converts phosphatidylinositol-(3,4,5)trisphosphate (generated by PI(3)K) into phosphatidylinositol-(3,4)-bisphosphate and thus inhibits downstream steps in the PI(3)K signaling pathway96.”
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Compartmentalized and systemic control of tissue immunity by commensals
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AhR sensing of bacterial pigments regulates antibacterial defence
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Innate Lymphoid Cells in Inflammation and Immunity
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Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation
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Evolution of Th2 Immunity: A Rapid Repair Response to Tissue Destructive Pathogens
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CD103− and CD103+ Bronchial Lymph Node Dendritic Cells Are Specialized in Presenting and Cross-Presenting Innocuous Antigen to CD4+ and CD8+ T Cells
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The T helper type 2 response to cysteine proteases requires dendritic cell–basophil cooperation via ROS-mediated signaling
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Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks.
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CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell–associated antigen
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Pattern recognition: recent insights from Dectin-1
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Beyond pattern recognition: five immune checkpoints for scaling the microbial threat
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The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice
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Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+ T cell responses to influenza
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BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway
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Virus-induced Interferon α Production by a Dendritic Cell Subset in the Absence of Feedback Signaling In Vivo
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Selective Utilization of Toll-like Receptor and MyD88 Signaling in B Cells for Enhancement of the Antiviral Germinal Center Response
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Innate immune detection of microbial nucleic acids
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Properdin: Emerging Roles of a Pattern-Recognition Molecule
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Pattern recognition receptor function in neutrophils
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TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses
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Tissue‐resident memory T cells
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GM-CSF–dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization
King, I. L., Kroenke, M. A., & Segal, B. M. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20091844 · Cited by 196 · see citing works
Missing self recognition and self tolerance of natural killer (NK) cells
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Host Defense Pathways: Role of Redundancy and Compensation in Infectious Disease Phenotypes
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Toll-Like Receptor Expression and Responsiveness of Distinct Murine Splenic and Mucosal B-Cell Subsets
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The interleukin‐23 axis in intestinal inflammation
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CD8α+ Dendritic Cells Are an Obligate Cellular Entry Point for Productive Infection by Listeria monocytogenes
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Effector-triggered versus pattern-triggered immunity: how animals sense pathogens
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Caspase-11 Activation in Response to Bacterial Secretion Systems that Access the Host Cytosol
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Reciprocal regulation of IL-23 and IL-12 following co-activation of Dectin-1 and TLR signaling pathways
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Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism
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Signals via the Adaptor MyD88 in B Cells and DCs Make Distinct and Synergistic Contributions to Immune Activation and Tissue Damage in Lupus
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Innate Lymphoid Cells: Balancing Immunity, Inflammation, and Tissue Repair in the Intestine
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Differential Requirements for NAIP5 in Activation of the NLRC4 Inflammasome
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Prostaglandins and sickness behavior: Old story, new insights
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Innate lymphoid cells: new insights into function and development
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Dendritic cell subsets require cis-activation for cytotoxic CD8 T-cell induction
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Batf3-Dependent CD11blow/− Peripheral Dendritic Cells Are GM-CSF-Independent and Are Not Required for Th Cell Priming after Subcutaneous Immunization
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B Cell Intrinsic MyD88 Signals Drive IFN-γ Production from T Cells and Control Switching to IgG2c
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Diversity of animal immune receptors and the origins of recognition complexity in the deuterostomes
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Cytokine-induced cytokine production by conventional and innate lymphoid cells
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Cell mediated immunity to fungi: a reassessment
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Guarding the perimeter: protection of the mucosa by tissue-resident memory T cells
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Toll-like Receptor 7 Controls the Anti-Retroviral Germinal Center Response
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Cytosolic surveillance and antiviral immunity
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Cutaneous basophil responses and immune resistance of guinea pigs to ticks: passive transfer with peritoneal exudate cells or serum.
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Antiviral Instruction of Bone Marrow Leukocytes during Respiratory Viral Infections
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Alveolar Macrophages and Lung Dendritic Cells Sense RNA and Drive Mucosal IgA Responses
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Activation of B lymphocytes: integrating signals from CD19, CD22 and FcγRIIb1
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Osteopontin expression by CD103 − dendritic cells drives intestinal inflammation
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Inflammation and tumor progression: signaling pathways and targeted intervention
Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y., & Li, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00658-5 · Cited by 2,907 · see citing works
Longitudinal analyses reveal immunological misfiring in severe COVID-19
Lucas, C., Wong, P., Klein, J., Castro, T. B. R., Silva, J., Sundaram, M., Ellingson, M. K., Mao, T., Oh, J. E., Israelow, B., et al. (2020) · Nature · doi:10.1038/s41586-020-2588-y · Cited by 2,074 · see citing works
Self-citation
The Sleep-Immune Crosstalk in Health and Disease
Besedovsky, L., Lange, T., & Haack, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00010.2018 · Cited by 1,479 · see citing works
“, intracellular (viral and bacterial) infection: type I IFNs/IL-12, Th1, IgG1, IgG3; helminth infection: IL-4, Th2, IgG4, IgE; fungal infection: IL-23, Th17], hallmarking the close interplay between the innate and adaptive arm of the immune system (266, 368, 566).”
Background
Consensus guidelines for the definition, detection and interpretation of immunogenic cell death
Galluzzi, L., Vitale, I., Warren, S., Adjemian, S., Agostinis, P., Buqué, A., Chan, T. A.-T., Coukos, G., Demaria, S., Deutsch, É., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000337 · Cited by 1,151 · see citing works
“221 Conversely, the microenvironment of dying cancer cells is a major determinant of their ability to initiate adaptive immune responses, even in the presence of sufficient antigenicity and adjuvanticity, 5 222 and this has major implications for the choice of experimental models for the assessment…”
Phagocytosis: An Immunobiologic Process
Gordon, S. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.026 · Cited by 902 · see citing works
“Iwasaki and Medzhitov have summarized in detail how specialized DC populations sense the nature of microbial intracellular infection to activate appropriate effector responses (Iwasaki and Medzhitov, 2015).”
Background
Advances in Biomaterials for Drug Delivery
Fenton, O. S., Olafson, K. N., Pillai, P. S., Mitchell, M. J., & Langer, R. (2018) · Advanced Materials · doi:10.1002/adma.201705328 · Cited by 869 · see citing works
Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors
Roybal, K. T., Williams, J. Z., Morsut, L., Rupp, L. J., Kolinko, I., Choe, J. H., Walker, W. J., McNally, K. A., & Lim, W. A. (2016) · Cell · doi:10.1016/j.cell.2016.09.011 · Cited by 723 · see citing works
“The specific cytokine profile is critical for eradicating pathogens and tumors (Dranoff, 2004; Iwasaki and Medzhitov, 2015).”
Anti-Inflammatory Action and Mechanisms of Resveratrol
Meng, T., Xiao, D., Muhammed, A., Deng, J., Chen, L., & He, J. (2021) · Molecules · doi:10.3390/molecules26010229 · Cited by 730 · see citing works
Immunity, inflammation, and cancer: an eternal fight between good and evil.
Shalapour, S., & Karin, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80007 · Cited by 641 · see citing works
The cGAS–STING pathway and cancer
Samson, N., & Ablasser, A. (2022) · Nature Cancer · doi:10.1038/s43018-022-00468-w · Cited by 705 · see citing works
Phagocytosis: Our Current Understanding of a Universal Biological Process
Uribe-Querol, E., & Rosales, C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01066 · Cited by 651 · see citing works
“Nevertheless, TLRs can cooperate with phagocytic receptors to make phagocytosis more eﬃcient (9).”
Background
Post-Translational Modification Control of Innate Immunity
Liu, J., Qian, C., & Cao, X. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.020 · Cited by 632 · see citing works
“Other PRRs include c-type lectin receptors (CLRs), formyl peptide receptors, complement receptors, signaling lymphocyte activation molecules (SLAMs), and numerous innate sensors for cytoplasmic nucleic acids (Takeuchi and Akira, 2010; Iwasaki and Medzhitov, 2015).”
Background
Acute-on-chronic liver failure: an update
Hernáez, R., Solà, E., Moreau, R., & Ginès, P. (2017) · Gut · doi:10.1136/gutjnl-2016-312670 · Cited by 612 · see citing works
“32 PRRs include toll-like receptors (TLRs), nucleotide-binding oligomerisation domain-like receptors (NLRs), retinoic acid-inducible gene (RIG)-”
BackgroundInfluential
Benefits and Inputs From Lactic Acid Bacteria and Their Bacteriocins as Alternatives to Antibiotic Growth Promoters During Food-Animal Production
Vieco-Saiz, N., Belguesmia, Y., Raspoet, R., Auclair, E., Gancel, F., Kempf, I., & Drider, D. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.00057 · Cited by 606 · see citing works
“In addition, the detection of microbes by PRR expressed in antigen-presenting cells, particularly dendritic cells (DC), leads to the activation of adaptive immune responses, by means of T and B cells (Iwasaki and Medzhitov, 2015).”
Background
Allergic inflammatory memory in human respiratory epithelial progenitor cells
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Antibiotic resistance genes from livestock waste: occurrence, dissemination, and treatment
He, Y., Yuan, Q., Mathieu, J., Stadler, L. B., Senehi, N. L., Sun, R., & Alvarez, P. J. J. (2020) · npj Clean Water · doi:10.1038/s41545-020-0051-0 · Cited by 598 · see citing works
“On the other hand, several ARB harbored by livestock may not infect humans due to maladaptation,(11) infection barriers(101) and immune response.(102) For example, a study of LAMRSA showed that while its presence in farm workers was highly correlated with duration of animal contact, it did not persist long once animal…”
Background
The multiple pathways to autoimmunity
Theofilopoulos, A. N., Kono, D. H., & Baccala, R. (2017) · Nature Immunology · doi:10.1038/ni.3731 · Cited by 590 · see citing works
Effects of Omega-3 Fatty Acids on Immune Cells
Gutiérrez, S., Svahn, S. L., & Johansson, M. E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205028 · Cited by 588 · see citing works
An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells
Zanoni, I., Tan, Y., Di Gioia, M., Broggi, A., Ruan, J., Shi, J., Donado, C. A., Shao, F., Wu, H., Springstead, J. R., et al. (2016) · Science · doi:10.1126/science.aaf3036 · Cited by 583 · see citing works
Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies
Patel, S. A., & Minn, A. J. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.007 · Cited by 574 · see citing works
“Conceptually, these discriminatory functions likely evolved to balance the “cost” associated with immune effector responses – specifically, direct detrimental effects of pathogens versus immunopathology from excessive immune stimulation (Iwasaki and Medzhitov, 2015).”
Background
Immunosenescence and human vaccine immune responses
Crooke, S. N., Ovsyannikova, I. G., Poland, G. A., & Kennedy, R. B. (2019) · Immunity & Ageing · doi:10.1186/s12979-019-0164-9 · Cited by 530 · see citing works
Complement in disease: a defence system turning offensive
Ricklin, D., Reis, E. S., & Lambris, J. D. (2016) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.70 · Cited by 558 · see citing works
Phagocytosis: A Fundamental Process in Immunity
Rosales, C., & Uribe‐Querol, E. (2017) · BioMed Research International · doi:10.1155/2017/9042851 · Cited by 555 · see citing works
“However, TLRs often collaborate with other nonopsonic receptors to stimulate ingestion [8].”
Background
Dendritic cell migration in inflammation and immunity
Liu, J., Zhang, X., Cheng, Y., & Cao, X. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00726-4 · Cited by 543 · see citing works
“In particular, CCR7dependent DC migration from peripheral tissues to lymphoid tissues is essential for host defense against pathogens and immune tolerance of harmless self- or nonself-antigens [3].”
Background
A history of exploring cancer in context
Maman, S., & Witz, I. P. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0006-7 · Cited by 502 · see citing works
mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases
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“These are factors crucial to successful induction of effective adaptive responses against the encoded antigen.(26) Currently, two forms of mRNA vaccines have been developed: conventional mRNA encoding the antigen of interest flanked by 50 and 30 UTRs, and self-amplifying mRNA derived from the genome of positive-strand…”
Background
Intratumoural administration and tumour tissue targeting of cancer immunotherapies
Melero, I., Álvarez, E. C., Álvarez, M., Champiat, S., & Marabelle, A. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00507-y · Cited by 492 · see citing works
Host–microbiota interactions in immune-mediated diseases
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Neuropeptide substance P and the immune response
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“These communications precede recruitment of non-resident immune cells and may lead to the development of adaptive immune responses [89, 90].”
Ubiquitin signaling in immune responses
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Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury
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“In a 2-tiered hierarchy of immune surveillance proposed by Iwasaki and Medzhitov (44), the EC should be included not only as an “effector cell” regulating influx of inflammatory cells and fluid and plasma proteins into tissue, but also as a cell capable of sensing intracellular LPS and activating pyroptosis.”
MethodInfluential
Protecting the Newborn and Young Infant from Infectious Diseases: Lessons from Immune Ontogeny
Kollmann, T. R., Kampmann, B., Mazmanian, S. K., Marchant, A., & Levy, O. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.009 · Cited by 478 · see citing works
Trained immunity — basic concepts and contributions to immunopathology
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Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics
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“Among them, NK-kB-dependent in ﬂ ammatory cytokines include TNF α , IL-1, and IL-6 21 .”
BackgroundInfluential
Cirrhosis-associated immune dysfunction
Albillos, A., Martín‐Mateos, R., der Merwe, V., Wiest, R., Jalan, R., & Álvarez‐Mon, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00520-7 · Cited by 461 · see citing works
ILC1 Confer Early Host Protection at Initial Sites of Viral Infection
Weizman, O.-E., Adams, N. M., Schuster, I. S., Krishna, C., Pritykin, Y., Lau, C. M., Degli‐Esposti, M. A., Leslie, C. S., Sun, J. C.-Y., & O’Sullivan, T. E. (2017) · Cell · doi:10.1016/j.cell.2017.09.052 · Cited by 454 · see citing works
“Because initial viral entry predominantly occurs at mucosal surfaces (i.e., lung, skin, mouth) (Iwasaki and Medzhitov, 2015), we also tested whether lung resident NK1.”
Mung Bean (Vigna radiata L.): Bioactive Polyphenols, Polysaccharides, Peptides, and Health Benefits
Hou, D., Yousaf, L., Xue, Y., Hu, J., Wu, J., Hu, X., Feng, N., & Shen, Q. (2019) · Nutrients · doi:10.3390/nu11061238 · Cited by 454 · see citing works
“Traditionally, immune processes have been divided into two broad, but interconnected, subsystems on the basis of their functions in host defense, namely innate and adaptive immunity [116].”
Background
Multifunctional GelMA platforms with nanomaterials for advanced tissue therapeutics
Kurian, A. G., Singh, R. K., Patel, K. D., Lee, J., & Kim, H. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.06.027 · Cited by 450 · see citing works
Acute-on-chronic liver failure in cirrhosis
Arroyo, V., Moreau, R., Kamath, P. S., Jalan, R., Ginès, P., Nevens, F., Fernández, J., To, U. K., García–Tsao, G., & Schnabl, B. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.41 · Cited by 442 · see citing works
Lung microbiome: new insights into the pathogenesis of respiratory diseases
Li, R., Li, J., & Zhou, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01722-y · Cited by 466 · see citing works
“176 Moreover, microbiota-produced metabolites are also associated with the immune response.”
Background
Toll-like Receptor Signaling Rewires Macrophage Metabolism and Promotes Histone Acetylation via ATP-Citrate Lyase
Lauterbach, M. A. R., Hanke, J. E., Serefidou, M., Mangan, M., Kolbe, C., Hess, T., Rothe, M., Kaiser, R., Hoß, F., Gehlen, J., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.11.009 · Cited by 436 · see citing works
Innate immunity in vertebrates: an overview
Riera‐Romo, M., Pérez‐Martínez, D., & Ferrer, C. C. (2016) · Immunology · doi:10.1111/imm.12597 · Cited by 437 · see citing works
The Formation and Function of Granulomas
Pagán, A. J., & Ramakrishnan, L. (2018) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-100022 · Cited by 431 · see citing works
Balancing the immune response in the brain: IL-10 and its regulation
Lobo‐Silva, D., Carriche, G. M., Castro, A. G., Roque, S., & Saraiva, M. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0763-8 · Cited by 427 · see citing works
“Innate immune cells express a wide variety of pattern recognition receptors (PRRs) which, upon recognition of danger signals, trigger a series of intracellular cascades that culminate with the production of immune mediators, among which pro- and anti-inflammatory cytokines [15].”
Background
Sensing Danger: Key to Activating Plant Immunity
Gust, A. A., Pruitt, R. N., & Nürnberger, T. (2017) · Trends in Plant Science · doi:10.1016/j.tplants.2017.07.005 · Cited by 401 · see citing works
Mitochondria in innate immune signaling
Banoth, B., & Cassel, S. L. (2018) · Translational Research · doi:10.1016/j.trsl.2018.07.014 · Cited by 410 · see citing works
Tailoring Materials for Modulation of Macrophage Fate
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Intracellular Pathogens: Host Immunity and Microbial Persistence Strategies
Thakur, A., Mikkelsen, H., & Jungersen, G. (2019) · Journal of Immunology Research · doi:10.1155/2019/1356540 · Cited by 404 · see citing works
“Innate and adaptive immune systems are linked, and innate immune recognition controls activation of adaptive immune responses [8].”
Background
Innate Immunity and Breast Milk
Cacho, N. T., & Lawrence, R. M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00584 · Cited by 396 · see citing works
“Although research into the specific factors in human breast milk, which lead to the remarkable health benefits of exclusive breastfeeding, has been ongoing for decades; there are still intriguing mysteries of how human milk contributes to the development and regulation of both the infant’s innate (10) and adaptive imm…”
Background
Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy
Patente, T. A., Pinho, M. P., Oliveira, A. A., Evangelista, G. C. M., Bergami-Santos, P. C., & Barbuto, J. A. M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03176 · Cited by 393 · see citing works
“When interacting with CD4+ T cells, DC may induce their differentiation into different T helper (Th) subsets (52) such as Th1 (55–60), Th2 (56, 57, 61, 62), Th17 (63–65), or other CD4+ T cell subtypes (66) (Figure 2).”
Background
Neutrophils at the crossroads of innate and adaptive immunity
Rosales, C. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.4mir0220-574rr · Cited by 372 · see citing works
New frontiers in the cGAS-STING intracellular DNA-sensing pathway
Dvorkin, S., Cambier, S., Volkman, H. E., & Stetson, D. B. (2024) · Immunity · doi:10.1016/j.immuni.2024.02.019 · Cited by 377 · see citing works
Constitutive immune mechanisms: mediators of host defence and immune regulation
Paludan, S. R., Pradeu, T., Masters, S. L., & Mogensen, T. H. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0391-5 · Cited by 363 · see citing works
Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies
Chew, H., Solomon, V. A., & Fonteh, A. N. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00598 · Cited by 353 · see citing works
“responsible for activating the adaptive immune system, which is slower due to the lengthy production of specific antibodies to the foreign antigen (Iwasaki and Medzhitov, 2015).”
Background
Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses
Grandi, N., & Tramontano, E. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02039 · Cited by 346 · see citing works
“In both cases, PRR stimulation by microbial PAMPs activates a complex cascade of signaling that triggers the production of various pro-inflammatory molecules, including cytokines, chemokines and type I IFN (78, 79).”
Background
Innate-adaptive immunity interplay and redox regulation in immune response
Sun, L., Wang, X., Saredy, J., Yuan, Z., Yang, X., & Wang, H. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101759 · Cited by 343 · see citing works
The influence of skin microorganisms on cutaneous immunity
Belkaid, Y., & Tamoutounour, S. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.48 · Cited by 336 · see citing works
Early local immune defences in the respiratory tract
Iwasaki, A., Foxman, E. F., & Molony, R. D. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.117 · Cited by 330 · see citing works
Self-citation
Inflammasomes in chronic liver disease: hepatic injury, fibrosis progression and systemic inflammation
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Dendritic cells as shepherds of T cell immunity in cancer
Pittet, M. J., Pilato, M. D., Garris, C., & Mempel, T. R. (2023) · Immunity · doi:10.1016/j.immuni.2023.08.014 · Cited by 326 · see citing works
Role of Human Milk Bioactives on Infants' Gut and Immune Health
Carr, L. E., Virmani, M., da Rosa, F. T., Munblit, D., Matazel, K. S., Elolimy, A. A., & Yeruva, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.604080 · Cited by 328 · see citing works
“The questions that remain unanswered are: (1) what combination of HMOs or their derivatives should be added to standard formula? (2) should HMOs be added to formula for premature infants? (3) what are the direct and indirect effects of HMOs on infant immune function? (4) how does maternal microbiota transfer into milk…”
Background
Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens
Perner, C., Flayer, C. H., Zhu, X., Aderhold, P. A., Dewan, Z. N. A., Voisin, T., Camire, R. B., Chow, O. A., Chiu, I. M., & Sokol, C. L. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.001 · Cited by 320 · see citing works
“In the classical PAMP-PRR signaling paradigm, tissue DCs act as direct sensors of type-1 immunogens, such as bacteria and viruses, to initiate adaptive immune responses (Iwasaki and Medzhitov, 2015).”
Background
The interaction of innate immune and adaptive immune system
Wang, R., Lan, C., Benlagha, K., Câmara, N. O. S., Miller, H. E., Kubo, M., Heegaard, S., Lee, P. P. W., Yang, L., Forsman, H. F., et al. (2024) · MedComm · doi:10.1002/mco2.714 · Cited by 355 · see citing works
Control of Phagocytosis by Microbial Pathogens
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“Toll-like receptors (TLRs), although recognize microorganisms, do not function as phagocytic receptors (32), however, they can cooperate with other non-opsonic receptors to stimulate phagocytosis (33).”
Background
Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization
Wang, N., Chen, M., & Wang, T. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.04.025 · Cited by 310 · see citing works
“Whilst the adaptive immune system has evolved for around 500 million years and is confined to vertebrates, the innate immune system has been established for a much longer time and acts as the main defensive strategy among vertebrates, invertebrates, as well as in plants, under modulation by rather conserved mechanisms…”
Background
Recent advances in dynamic m 6 A RNA modification
Cao, G., Li, H., Yin, Z., & Flavell, R. A. (2016) · Open Biology · doi:10.1098/rsob.160003 · Cited by 305 · see citing works
Interconnections between Inflammageing and Immunosenescence during Ageing
Teissier, T., Boulanger, É., & Cox, L. S. (2022) · Cells · doi:10.3390/cells11030359 · Cited by 310 · see citing works
“Common lymphoid progenitors (CLPs) in the bone marrow produce small lymphocytes that will become B cells if processed in the bone marrow [313] or T cells if processed in the thymus [314].”
Background
Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes
Cerboni, S., Jeremiah, N., Gentili, M., Gehrmann, U., Conrad, C., Stolzenberg, M., Pïcard, C., Neven, B., Fischer, A., Amigorena, S., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20161674 · Cited by 303 · see citing works
“DC activation also typically requires NF-κB signaling (Janeway and Medzhitov, 2002).”
Background
Immunological Approaches Towards Cancer and Inflammation: A Cross Talk
Qu, X., Tang, Y., & Hua, S. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00563 · Cited by 301 · see citing works
“The innate immune system confronts pathogens via a large number of diverse pathogen-recognition receptors (PRRs) and by the generation of nonselective and random antigen-specific receptors molecules (81).”
BackgroundInfluential
Inflammation and preterm birth
Cappelletti, M., Bella, S. D., Ferrazzi, E. M., Mavilio, D., & Divanovic, S. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3mr0615-272rr · Cited by 297 · see citing works
“manuscript and has been discussed in detail elsewhere [59, 60].”
Background
Neuro-Immune Interactions at Barrier Surfaces
Veiga‐Fernandes, H., & Mucida, D. (2016) · Cell · doi:10.1016/j.cell.2016.04.041 · Cited by 290 · see citing works
An Update on Self-Amplifying mRNA Vaccine Development
Blakney, A. K., Ip, S., & Geall, A. J. (2021) · Vaccines · doi:10.3390/vaccines9020097 · Cited by 288 · see citing works
“dendritic cells (DCs), leads to the activation of adaptive immune responses.[53] Over the last 5 years, saRNA vaccine mechanism of action studies and a better understanding of the RNA”
Background
The how and why of lncRNA function: An innate immune perspective
Robinson, E. K., Covarrubias, S., & Carpenter, S. (2019) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2019.194419 · Cited by 278 · see citing works
“The innate immune system functions as a rapid initial response against specific pathogens, while also promoting the activation and development of the adaptive immune system [18].”
Unique aspects of the perinatal immune system
Zhang, X., Zhivaki, D., & Lo-Man, R. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.54 · Cited by 276 · see citing works
Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control
Gideon, H. P., Hughes, T. K., Tzouanas, C. N., Wadsworth, M. H., Tu, A. A., Gierahn, T. M., Peters, J. M., Hopkins, F. F., Wei, J.-R., Kummerlowe, C., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.04.004 · Cited by 278 · see citing works
“Beyond recapitulating canonical correlates, our analysis defined nuanced, actionable, innate as well as adaptive functional cell states and shed light on essential dynamics among host-pathogen interactions (Iwasaki and Medzhitov, 2015).”
Background
Natural and synthetic carbohydrate-based vaccine adjuvants and their mechanisms of action
Pifferi, C., Fuentes, R., & Fernández‐Tejada, A. (2021) · Nature Reviews Chemistry · doi:10.1038/s41570-020-00244-3 · Cited by 270 · see citing works
Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease
Hegyi, P., Maléth, J., Walters, J. R., Hofmann, A. F., & Keely, S. J. (2018) · Physiological Reviews · doi:10.1152/physrev.00054.2017 · Cited by 269 · see citing works
Role of the NLRP3 inflammasome in autoimmune diseases
Li, Z., Guo, J., & Bi, L. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110542 · Cited by 268 · see citing works
Immune Modulation by Volatile Anesthetics
Stollings, L., Jia, L., Tang, P. S., Dou, H., Lu, B., & Xu, Y. (2016) · Anesthesiology · doi:10.1097/aln.0000000000001195 · Cited by 263 · see citing works
Controlling timing and location in vaccines
Irvine, D. J., Aung, A., & Silva, M. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.019 · Cited by 251 · see citing works
“These antigen recognition eventsmust occur in the context inflammatory cues that direct the type of immune response the immune system should mount to the antigen [27]- such inflammatory cues come in the formofmolecules that activate innate immune system pattern recognition receptors (e.”
Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation
Schappe, M. S., Szteyn, K., Stremska, M. E., Mendu, S. K., Downs, T. K., Seegren, P. V., Mahoney, M. A., Dixit, S., Krupa, J. K., Stipes, E. J., et al. (2018) · Immunity · doi:10.1016/j.immuni.2017.11.026 · Cited by 251 · see citing works
“Cells of the innate immune system trigger finely tuned cellular responses for host defense while minimizing collateral damage to the host (Iwasaki and Medzhitov, 2015).”
Background
Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial
Lopes, M. I. F., Bonjorno, L. P., Giannini, M. C., do Amaral, N. B., Menezes, P. I., DIB, S. M., GIGANTE, S. L. G., Benatti, M. N., Rezek, U. C., Emrich-Filho, L. L., et al. (2021) · RMD Open · doi:10.1136/rmdopen-2020-001455 · Cited by 252 · see citing works
Physical activation of innate immunity by spiky particles
Wang, J., Chen, H., Hang, T., Yu, Y., Liu, G., He, G., Xiao, S., Yang, B., Yang, C., Liu, F., et al. (2018) · Nature Nanotechnology · doi:10.1038/s41565-018-0274-0 · Cited by 247 · see citing works
The functionality of prebiotics as immunostimulant: Evidences from trials on terrestrial and aquatic animals
Nawaz, A., Javaid, A. B., Irshad, S., Hoseinifar, S. H., & Xiong, H. (2018) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2018.03.004 · Cited by 242 · see citing works
Inflammasomes and adaptive immune responses
Deets, K. A., & Vance, R. E. (2021) · Nature Immunology · doi:10.1038/s41590-021-00869-6 · Cited by 238 · see citing works
Neuroimmunity: Physiology and Pathology
Talbot, S., Foster, S. L., & Woolf, C. J. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055340 · Cited by 239 · see citing works
Human IFNAR2 deficiency: Lessons for antiviral immunity
Duncan, C. J. A., Mohamad, S. M., Young, D. F., Skelton, A. J., Leahy, T. R., Munday, D. C., BUTLER, K. M., Morfopoulou, S., Brown, J. R., Hubank, M. J. F., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aac4227 · Cited by 237 · see citing works
“Furthermore, IFNs contribute to the recruitment and activation of both innate and adaptive immune effectors (2, 3).”
Background
Toll-like receptor 4–mediated lymphocyte influx induces neonatal necrotizing enterocolitis
Egan, C. E., Sodhi, C. P., Good, M. L., Lin, J., Jia, H., Yamaguchi, Y., Lu, P., Ma, C., Branca, M. F., Weyandt, S., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83356 · Cited by 233 · see citing works
“We now hypothesize that the inflammatory cells found in the intestinal mucosa of patients and mice with NEC (19, 20) are actually primary instigators of this disease process and are regulated by TLR4 on the intestinal epithelium (21).”
Mechanism of action of mRNA-based vaccines
Iavarone, C., O’hagan, D. T., Yu, D., Delahaye, N. F., & Ulmer, J. B. (2017) · Expert Review of Vaccines · doi:10.1080/14760584.2017.1355245 · Cited by 234 · see citing works
“Interaction among PRRs and PAMPs triggers the inflammatory response, the link between the innate immunity and the adaptive immunity [43].”
Background
Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities
Hayn, M., Hirschenberger, M., Koepke, L., Nchioua, R., Straub, J. H., Klute, S., Hunszinger, V., Zech, F., Bozzo, C. P., Aftab, W., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109126 · Cited by 225 · see citing works
Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies
Gujar, S. A., Pol, J. G., Kim, Y., Lee, P. W. K., & Kroemer, G. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.11.006 · Cited by 234 · see citing works
Immune System Dysfunction in the Elderly
Eduardo Fuentes, Q., FUENTES, M., Alarcón, M. A., & Palomo, I. F. (2017) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765201720160487 · Cited by 234 · see citing works
Pas de Deux: Control of Anti-tumor Immunity by Cancer-Associated Inflammation
Shalapour, S., & Karin, M. (2019) · Immunity · doi:10.1016/j.immuni.2019.06.021 · Cited by 229 · see citing works
“At each phase, acute inflammation has different effects on either cellular or humoral immunity (Iwasaki and Medzhitov, 2015).”
Background
Innate immune sensing of coronavirus and viral evasion strategies
Kasuga, Y., Zhu, B., Jang, K., & Yoo, J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00602-1 · Cited by 230 · see citing works
The Regulation of Inflammation by Innate and Adaptive Lymphocytes
Cronkite, D. A., & Strutt, T. M. (2018) · Journal of Immunology Research · doi:10.1155/2018/1467538 · Cited by 228 · see citing works
“They employ germ-line encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular pattern (PAMPs) [32] and damage-associated molecular pathogens (DAMP) [33, 34] to detect changes in their environment [35, 36].”
The role of declining adaptive homeostasis in ageing
Pomatto, L. C. D., & Davies, K. J. A. (2017) · The Journal of Physiology · doi:10.1113/jp275072 · Cited by 223 · see citing works
“…acute phases: (1) detection of pathogen-associated molecular patterns (PAMPs), (2) mediated by pattern-recognition receptors (PRRs) (Kawai & Akira, 2010); (3) PRRs in turn release specific cytokines, which cause lymphocyte differentiation specific to the type of insult (Iwasaki & Medzhitov, 2015).”
Background
Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy
Liu, Y., Qiao, L., Zhang, S., Wan, G., Chen, B., Zhou, P., Zhang, N., & Wang, Y. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.11.010 · Cited by 218 · see citing works
Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ–IRF3 axis activation
Tsukamoto, H., Takeuchi, S., Kubota, K., Kobayashi, Y., Kozakai, S., Ukai, I., Shichiku, A., Okubo, M., Numasaki, M., Kanemitsu, Y., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.796631 · Cited by 215 · see citing works
“The induction of cytokines and chemokines by the innate immune system causes inflammation and initiates adaptive immunity (3).”
Background
Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection
Steinbach, K., Vincenti, I., Kreutzfeldt, M., Pagé, N., Muschaweckh, A., Wagner, I., Drexler, I., Pinschewer, D. D., Korn, T., & Merkler, D. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20151916 · Cited by 212 · see citing works
“In naive hosts, the task of rapidly detecting invading pathogens and alerting the adaptive immune defense generally falls to the innate immune system (Iwasaki and Medzhitov, 2015).”
Background
Interleukin-1 as Innate Mediator of T Cell Immunity
Eeckhout, B. V. D., Tavernier, J. H., & Gerlo, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.621931 · Cited by 211 · see citing works
“This information transfer happens over three major routes: (1) presentation of antigenic peptides to antigen-specific T cells, resulting in an antigen-specific response; (2) co-stimulation, which can be perceived as qualitative information on the context of the antigen and allows for breaking tolerance; and (3) releas…”
BackgroundInfluential

Authors: Iwasaki, A., & Medzhitov, R.
Affiliations: Howard Hughes Medical Institute (US)
Corresponding author: Iwasaki, Akiko
Medzhitov, Ruslan
ORCID: Iwasaki, Akiko
Medzhitov, Ruslan
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2015-03-19
Volume: 16
Issue: 4
Pages: 343-353
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.3123
PMC: PMC4507498
OpenAlex: W2044757050
Cited by: 2,160
References: 139
Citations by year: 2026: 183 · 2025: 212 · 2024: 181 · 2023: 193 · 2022: 204 · 2021: 239 · 2020: 216 · 2019: 189 · 2018: 187 · 2017: 167 · 2016: 157 · 2015: 31 · 2012: 1
FWCI: 17.06
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Institute of Allergy and Infectious Diseases (R01AI064705, AI062428, AI 064705, R01AI062428, AI 081884, R56AI062428, AI089771, R01AI089771, R01AI054359, R37AI046688, AI046688, R01AI081884, R01AI046688)
National Institute of Diabetes and Digestive and Kidney Diseases (DK071754, R01DK071754)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords: innate immunity, adaptive immunity, innate-adaptive immune crosstalk, pathogen recognition, dendritic cells, cytokines, lymphocyte activation, microbial infection, pattern recognition receptors
MeSH terms: Animals, Bacteria, Dendritic Cells, Fungi, Gene Expression Regulation, Helminths, Humans, Immunity, Innate, Intestines, Lung, Skin, Viruses, Lymphocyte Subsets, Cytokines, Receptors, Pattern Recognition, Adaptive Immunity

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Control of adaptive immunity by the innate immune system

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