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Annu Rev Immunol 2022 Apr;40:295-321

Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; email:

Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Read More

Annu Rev Immunol 2022 Apr;40:45-74

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA; email:

The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Read More

Annu Rev Immunol 2022 Apr;40:499-523

Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; email:

The bladder is a major component of the urinary tract, an organ system that expels metabolic waste and excess water, which necessitates proximity to the external environment and its pathogens. It also houses a commensal microbiome. Therefore, its tissue immunity must resist pathogen invasion while maintaining tolerance to commensals. Read More

Annu Rev Immunol 2022 Apr;40:95-119

Centre d'Immunologie de Marseille-Luminy (CIML), CNRS, INSERM, Aix-Marseille Université, Marseille, France; email:

A high diversity of αβ T cell receptors (TCRs), capable of recognizing virtually any pathogen but also self-antigens, is generated during T cell development in the thymus. Nevertheless, a strict developmental program supports the selection of a self-tolerant T cell repertoire capable of responding to foreign antigens. The steps of T cell selection are controlled by cortical and medullary stromal niches, mainly composed of thymic epithelial cells and dendritic cells. Read More

Annu Rev Immunol 2022 Apr;40:443-467

Laboratory of Mucosal Immunology and Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium; email:

A principal purpose of type 2 immunity was thought to be defense against large parasites, but it also functions in the restoration of homeostasis, such as toxin clearance following snake bites. In other cases, like allergy, the type 2 T helper (Th2) cytokines and cells present in the environment are detrimental and cause diseases. In recent years, the recognition of cell heterogeneity within Th2-associated cell populations has revealed specific functions of cells with a particular phenotype or gene signature. Read More

Annu Rev Immunol 2022 Apr 9;40:469-498. Epub 2022 Apr 9.

Department of Immunology and Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA; email:

Intracellular pathogens pose a significant threat to animals. In defense, innate immune sensors attempt to detect these pathogens using pattern recognition receptors that either directly detect microbial molecules or indirectly detect their pathogenic activity. These sensors trigger different forms of regulated cell death, including pyroptosis, apoptosis, and necroptosis, which eliminate the infected host cell niche while simultaneously promoting beneficial immune responses. Read More

Annu Rev Immunol 2022 Apr 8;40:615-649. Epub 2022 Feb 8.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; email:

Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by arthritogenic and encephalitic alphaviruses results in distinct clinical manifestations, both virus groups induce robust innate and adaptive immune responses. However, differences in cellular tropism, type I interferon induction, immune cell recruitment, and B and T cell responses result in differential disease progression and outcome. Read More

Annu Rev Immunol 2022 Apr 7;40:525-557. Epub 2022 Feb 7.

Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.

Macrophages and conventional dendritic cells (cDCs) are distributed throughout the body, maintaining tissue homeostasis and tolerance to self and orchestrating innate and adaptive immunity against infection and cancer. As they complement each other, it is important to understand how they cooperate and the mechanisms that integrate their functions. Both are exposed to commensal microbes, pathogens, and other environmental challenges that differ widely among anatomical locations and over time. Read More

Annu Rev Immunol 2022 Apr 7;40:589-614. Epub 2022 Feb 7.

Seattle Children's Research Institute, Seattle, Washington, USA; email:

Pulmonary granulomas are widely considered the epicenters of the immune response to (Mtb), the causative agent of tuberculosis (TB). Recent animal studies have revealed factors that either promote or restrict TB immunity within granulomas. These models, however, typically ignore the impact of preexisting immunity on cellular organization and function, an important consideration because most TB probably occurs through reinfection of previously exposed individuals. Read More

Annu Rev Immunol 2022 Apr 4;40:387-411. Epub 2022 Feb 4.

Department of Microbial Infection and Immunity and Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, Ohio, USA; email:

Cell identity and function largely rely on the programming of transcriptomes during development and differentiation. Signature gene expression programs are orchestrated by regulatory circuits consisting of acting promoters and enhancers, which respond to a plethora of cues via the action of transcription factors. In turn, transcription factors direct epigenetic modifications to revise chromatin landscapes, and drive contacts between distal promoter-enhancer combinations. Read More

Annu Rev Immunol 2022 Apr 3;40:559-587. Epub 2022 Feb 3.

Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. Read More

Annu Rev Immunol 2022 Apr 3;40:413-442. Epub 2022 Feb 3.

Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA; email:

Germinal centers (GCs) are microanatomical sites of B cell clonal expansion and antibody affinity maturation. Therein, B cells undergo the Darwinian process of somatic diversification and affinity-driven selection of immunoglobulins that produces the high-affinity antibodies essential for effective humoral immunity. Here, we review recent developments in the field of GC biology, primarily as it pertains to GCs induced by infection or immunization. Read More

Annu Rev Immunol 2022 Apr 3;40:349-386. Epub 2022 Feb 3.

Vanderbilt Vaccine Center, Department of Pediatrics, and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; email:

Antibodies have been used to prevent or treat viral infections since the nineteenth century, but the full potential to use passive immunization for infectious diseases has yet to be realized. The advent of efficient methods for isolating broad and potently neutralizing human monoclonal antibodies is enabling us to develop antibodies with unprecedented activities. The discovery of IgG Fc region modifications that extend antibody half-life in humans to three months or more suggests that antibodies could become the principal tool with which we manage future viral epidemics. Read More

Annu Rev Immunol 2022 Apr 3;40:323-348. Epub 2022 Feb 3.

Laboratory of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; email:

The diverse biological activity of interleukin-6 (IL-6) contributes to the maintenance of homeostasis. Emergent infection or tissue injury induces rapid production of IL-6 and activates host defense through augmentation of acute-phase proteins and immune responses. However, excessive IL-6 production and uncontrolled IL-6 receptor signaling are critical to pathogenesis. Read More

Annu Rev Immunol 2022 Apr 26;40:271-294. Epub 2022 Jan 26.

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; email:

Vertebrate immune systems suppress viral infection using both innate restriction factors and adaptive immunity. Viruses mutate to escape these defenses, driving hosts to counterevolve to regain fitness. This cycle recurs repeatedly, resulting in an evolutionary arms race whose outcome depends on the pace and likelihood of adaptation by host and viral genes. Read More

Annu Rev Immunol 2022 Apr 26;40:249-269. Epub 2022 Jan 26.

Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Australia; email:

Inflammasomes are inflammatory signaling complexes that provide molecular platforms to activate the protease function of inflammatory caspases. Caspases-1, -4, -5, and -11 are inflammatory caspases activated by inflammasomes to drive lytic cell death and inflammatory mediator production, thereby activating host-protective and pathological immune responses. Here, we comprehensively review the mechanisms that govern the activity of inflammatory caspases. Read More

Annu Rev Immunol 2022 Apr 21;40:221-247. Epub 2022 Jan 21.

Department of Structural Biology, Genentech, Inc., South San Francisco, California, USA.

As central effectors of the adaptive immune response, immunoglobulins, or antibodies, provide essential protection from pathogens through their ability to recognize foreign antigens, aid in neutralization, and facilitate elimination from the host. Mammalian immunoglobulins can be classified into five isotypes-IgA, IgD, IgE, IgG, and IgM-each with distinct roles in mediating various aspects of the immune response. Of these isotypes, IgA and IgM are the only ones capable of multimerization, arming them with unique biological functions. Read More

Annu Rev Immunol 2022 Apr 19;40:195-220. Epub 2022 Jan 19.

Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, USA; email:

Tissue-resident immune cells span both myeloid and lymphoid cell lineages, have been found in multiple human tissues, and play integral roles at all stages of the immune response, from maintaining homeostasis to responding to infectious challenges to resolution of inflammation to tissue repair. In humans, studying immune cells and responses in tissues is challenging, although recent advances in sampling and high-dimensional profiling have provided new insights into the ontogeny, maintenance, and functional role of tissue-resident immune cells. Each tissue contains a specific complement of resident immune cells. Read More

Annu Rev Immunol 2022 Apr 19;40:169-193. Epub 2022 Jan 19.

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; email:

The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. Read More

Annu Rev Immunol 2022 Apr 10;40:121-141. Epub 2022 Jan 10.

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; email:

Invasive fungal diseases are rare in individuals with intact immunity. This, together with the fact that there are only a few species that account for most mycotic diseases, implies a remarkable natural resistance to pathogenic fungi. Mammalian immunity to fungi rests on two pillars, powerful immune mechanisms and elevated temperatures that create a thermal restriction zone for most fungal species. Read More

Annu Rev Immunol 2022 Apr 6;40:143-167. Epub 2022 Jan 6.

Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA; email:

The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Read More

Annu Rev Immunol 2022 Apr 5;40:75-94. Epub 2022 Jan 5.

Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA; email:

Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed that sex differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains to be learned about the mechanisms underlying associations between sex differences and immune-mediated conditions. Read More

Annu Rev Immunol 2022 Apr 5;40:15-43. Epub 2022 Jan 5.

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; email:

Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. Read More

Annu Rev Immunol 2022 Apr 6;40:1-14. Epub 2021 Dec 6.

Department of Immunology, University of Washington, Seattle, Washington, USA; email:

I've had serious misgivings about writing this article, because from living the experience day by day, it's hard to believe my accomplishments merit the attention. To skirt this roadblock, I forced myself to pretend I was in a conversation with my trainees, trying to distill the central driving forces of my career in science. The below chronicles my evolution from would-be astronaut/ballerina to budding developmental biologist to devoted T cell immunologist. Read More

Annu Rev Immunol 2021 04 3;39:v-vii. Epub 2021 May 3.

Molecular Immunology and Inflammation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland 20892, USA; email:

Annu Rev Immunol 2021 04;39:395-416

Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; email:

Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function. Read More

Annu Rev Immunol 2021 04;39:1-18

Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California 95616, USA; email:

An imbalance in the microbiota may contribute to many human illnesses, which has prompted efforts to rebalance it by targeting the microbes themselves. However, by supplying the habitat, the host wields a prominent influence over microbial growth at body surfaces, raising the possibility that rebalancing the microbiota by targeting our immune system would be a viable alternative. Host control mechanisms that sculpt the microbial habitat form a functional unit with the microbiota, termed microbiota-nourishing immunity, that confers colonization resistance against pathogens. Read More

Annu Rev Immunol 2021 04;39:313-344

Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; email:

Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of a plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it fit a pro- versus anti-inflammatory paradigm. This review presents and discusses current knowledge on the developmental biology of macrophages from an evolutionary perspective focused on the function of macrophages, which may aid in study of developmental, inflammatory, tumoral, and degenerative diseases. We also propose a framework to investigate the functions of macrophages in vivo and discuss how inherited germline and somatic mutations may contribute to the roles of macrophages in diseases. Read More

Annu Rev Immunol 2021 04;39:417-447

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; email:

Natural killer (NK) cells are innate lymphocytes that provide critical host defense against pathogens and cancer. Originally heralded for their early and rapid effector activity, NK cells have been recognized over the last decade for their ability to undergo adaptive immune processes, including antigen-driven clonal expansion and generation of long-lived memory. This review presents an overview of how NK cells lithely partake in both innate and adaptive responses and how this versatility is manifest in human NK cell-mediated immunity. Read More

Annu Rev Immunol 2021 04;39:791-817

Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA; email:

Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. Read More