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1.
Annu Rev Immunol ; 42(1): 317-345, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38941605

ABSTRACT

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.


Subject(s)
Immunologic Memory , Memory T Cells , Humans , Animals , Memory T Cells/immunology , Memory T Cells/metabolism , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Organ Specificity/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Immunologic Surveillance
2.
Annu Rev Immunol ; 39: 313-344, 2021 04 26.
Article in English | MEDLINE | ID: mdl-33902313

ABSTRACT

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.


Subject(s)
Hematopoietic Stem Cells , Macrophages , Animals , Biology , Humans
3.
Annu Rev Immunol ; 38: 621-648, 2020 04 26.
Article in English | MEDLINE | ID: mdl-32017656

ABSTRACT

Vitiligo is an autoimmune disease of the skin that targets pigment-producing melanocytes and results in patches of depigmentation that are visible as white spots. Recent research studies have yielded a strong mechanistic understanding of this disease. Autoreactive cytotoxic CD8+ T cells engage melanocytes and promote disease progression through the local production of IFN-γ, and IFN-γ-induced chemokines are then secreted from surrounding keratinocytes to further recruit T cells to the skin through a positive-feedback loop. Both topical and systemic treatments that block IFN-γ signaling can effectively reverse vitiligo in humans; however, disease relapse is common after stopping treatments. Autoreactive resident memory T cells are responsible for relapse, and new treatment strategies focus on eliminating these cells to promote long-lasting benefit. Here, we discuss basic, translational, and clinical research studies that provide insight into the pathogenesis of vitiligo, and how this insight has been utilized to create new targeted treatment strategies.


Subject(s)
Vitiligo/etiology , Vitiligo/therapy , Animals , Autoimmunity , Biomarkers , Cytokines/metabolism , Disease Management , Disease Susceptibility , Humans , Immunologic Memory , Vitiligo/diagnosis
4.
Annu Rev Immunol ; 35: 119-147, 2017 04 26.
Article in English | MEDLINE | ID: mdl-28125357

ABSTRACT

The intestinal epithelial barrier includes columnar epithelial, Paneth, goblet, enteroendocrine, and tuft cells as well as other cell populations, all of which contribute properties essential for gastrointestinal homeostasis. The intestinal mucosa is covered by mucin, which contains antimicrobial peptides and secretory IgA and prevents luminal bacteria, fungi, and viruses from stimulating intestinal immune responses. Conversely, the transport of luminal microorganisms-mediated by M, dendritic, and goblet cells-into intestinal tissues facilitates the harmonization of active and quiescent mucosal immune responses. The bacterial population within gut-associated lymphoid tissues creates the intratissue cohabitations for harmonized mucosal immunity. Intermolecular and intercellular communication among epithelial, immune, and mesenchymal cells creates an environment conducive for epithelial regeneration and mucosal healing. This review summarizes the so-called intestinal mucosal ecological network-the complex but vital molecular and cellular interactions of epithelial mesenchymal cells, immune cells, and commensal microbiota that achieve intestinal homeostasis, regeneration, and healing.


Subject(s)
Epithelial Cells/physiology , Gastrointestinal Microbiome/immunology , Intestinal Mucosa/immunology , Animals , Cell Communication , Homeostasis , Humans , Immunity, Innate , Immunoglobulin A/metabolism , Intestinal Mucosa/pathology , Wound Healing
5.
Annu Rev Immunol ; 34: 575-608, 2016 05 20.
Article in English | MEDLINE | ID: mdl-27168245

ABSTRACT

Mucosal surfaces provide a remarkably effective barrier against potentially dangerous pathogens. Therefore, enhancing mucosal immunity through vaccines-strengthening that first line of defense-holds significant promise for reducing the burden of viral diseases. The large and varied class of viral pathogens, however, continues to present thorny challenges to vaccine development. Two primary difficulties exist: Viruses exhibit a stunning diversity of strategies for evading the host immune response, and even when we understand the nature of effective immune protection against a given virus, eliciting that protection is technically challenging. Only a few mucosal vaccines have surmounted these obstacles thus far. Recent developments, however, could greatly improve vaccine design. In this review, we first sketch out our understanding of mucosal immunity and then compare the herpes simplex virus, human immunodeficiency virus, and influenza virus to illustrate the distinct challenges of developing successful vaccines and to outline potential solutions.


Subject(s)
HIV/immunology , Immune Evasion , Immunity, Mucosal , Orthomyxoviridae/immunology , Simplexvirus/immunology , Viral Vaccines/immunology , Virus Diseases/immunology , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Humans , Immunologic Memory , Virus Diseases/prevention & control
6.
Cell ; 185(7): 1189-1207.e25, 2022 03 31.
Article in English | MEDLINE | ID: mdl-35325594

ABSTRACT

Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.


Subject(s)
Breast Neoplasms , Macrophages , Breast/immunology , Breast Neoplasms/epidemiology , Breast Neoplasms/immunology , CD8-Positive T-Lymphocytes , Female , Folate Receptor 2 , Humans , Lymphocytes, Tumor-Infiltrating , Prognosis
7.
Cell ; 185(16): 2918-2935.e29, 2022 08 04.
Article in English | MEDLINE | ID: mdl-35803260

ABSTRACT

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.


Subject(s)
Neoplasms , Programmed Cell Death 1 Receptor , CD8-Positive T-Lymphocytes , Humans , Immunotherapy , Lymphocytes, Tumor-Infiltrating , Neoadjuvant Therapy , Neoplasms/therapy , Tumor Microenvironment
8.
Cell ; 183(5): 1282-1297.e18, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33098771

ABSTRACT

Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.


Subject(s)
Cell Lineage , Neutrophils/metabolism , Organ Specificity , Animals , Chromatin/metabolism , Female , Hematopoiesis , Intestines/blood supply , Lung/blood supply , Male , Mice, Inbred C57BL , Neovascularization, Physiologic , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Receptors, CXCR4/metabolism , Single-Cell Analysis , Transcription, Genetic , Transcriptome/genetics
9.
Cell ; 182(3): 625-640.e24, 2020 08 06.
Article in English | MEDLINE | ID: mdl-32702313

ABSTRACT

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.


Subject(s)
Brain/cytology , CD4-Positive T-Lymphocytes/metabolism , Fetus/cytology , Microglia/cytology , Microglia/metabolism , Synapses/metabolism , Adult , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Behavior Rating Scale , Blood Cells/cytology , Blood Cells/metabolism , Brain/embryology , Brain/metabolism , Child , Female , Fetus/embryology , Humans , Lectins, C-Type/metabolism , Lung/cytology , Lung/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neurogenesis/genetics , Parabiosis , Pyramidal Cells/metabolism , Pyramidal Cells/physiology , Single-Cell Analysis , Spleen/cytology , Spleen/metabolism , Synapses/immunology , Transcriptome
10.
Cell ; 182(3): 655-671.e22, 2020 08 06.
Article in English | MEDLINE | ID: mdl-32603654

ABSTRACT

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.


Subject(s)
CD8-Positive T-Lymphocytes/cytology , CTLA-4 Antigen/immunology , Colitis/metabolism , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Myeloid Cells/metabolism , Receptors, Chemokine/metabolism , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , CTLA-4 Antigen/metabolism , Chemokines/metabolism , Colitis/drug therapy , Colitis/genetics , Colitis/immunology , Cytokines/metabolism , Flow Cytometry , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Humans , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Melanoma/genetics , Melanoma/immunology , Melanoma/metabolism , Multigene Family , Myeloid Cells/cytology , RNA-Seq , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Receptors, CXCR3/genetics , Receptors, CXCR3/metabolism , Receptors, CXCR6/genetics , Receptors, CXCR6/metabolism , Receptors, Chemokine/genetics , Single-Cell Analysis , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism
11.
Cell ; 178(5): 1176-1188.e15, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31442406

ABSTRACT

Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing effector (TH17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exTH17 TRM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, γδ T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exTH17 TRM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design.


Subject(s)
Klebsiella Infections/immunology , Th17 Cells/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Diphtheria Toxin/pharmacology , Disease Models, Animal , Female , Immunologic Memory , Interleukin-17/genetics , Interleukin-17/metabolism , Klebsiella Infections/pathology , Klebsiella pneumoniae/immunology , Klebsiella pneumoniae/pathogenicity , Lung/drug effects , Lung/metabolism , Lung/microbiology , Mice , Mice, Inbred C57BL , Th17 Cells/cytology , Th17 Cells/metabolism
12.
Cell ; 176(5): 967-981.e19, 2019 02 21.
Article in English | MEDLINE | ID: mdl-30739797

ABSTRACT

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD. VIDEO ABSTRACT.


Subject(s)
Celiac Disease/immunology , Inflammation/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Antigens , Butyrophilins/metabolism , Celiac Disease/physiopathology , Chronic Disease , Diet, Gluten-Free , Glutens/metabolism , HEK293 Cells , Humans , Inflammation/metabolism , Intestinal Mucosa/immunology , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism
13.
Cell ; 177(3): 541-555.e17, 2019 04 18.
Article in English | MEDLINE | ID: mdl-30955887

ABSTRACT

Neutrophils are attracted to and generate dense swarms at sites of cell damage in diverse tissues, often extending the local disruption of organ architecture produced by the initial insult. Whether the inflammatory damage resulting from such neutrophil accumulation is an inescapable consequence of parenchymal cell death has not been explored. Using a combination of dynamic intravital imaging and confocal multiplex microscopy, we report here that tissue-resident macrophages rapidly sense the death of individual cells and extend membrane processes that sequester the damage, a process that prevents initiation of the feedforward chemoattractant signaling cascade that results in neutrophil swarms. Through this "cloaking" mechanism, the resident macrophages prevent neutrophil-mediated inflammatory damage, maintaining tissue homeostasis in the face of local cell injury that occurs on a regular basis in many organs because of mechanical and other stresses. VIDEO ABSTRACT.


Subject(s)
Macrophages/immunology , Neutrophils/immunology , Alarmins/metabolism , Animals , Endocytosis , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Muscle Fibers, Skeletal/pathology , Neutrophil Activation , Neutrophils/metabolism , Sialic Acid Binding Ig-like Lectin 1/metabolism
14.
Cell ; 178(6): 1509-1525.e19, 2019 09 05.
Article in English | MEDLINE | ID: mdl-31491389

ABSTRACT

Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes, and their functions compared to embryonic RTMs remain unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation, and disease are highly debated. Here, we identified Ms4a3 as a specific gene expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter, Ms4a3Cre, and Ms4a3CreERT2 fate-mapping models. These models traced efficiently monocytes and granulocytes, but no lymphocytes or tissue dendritic cells. Using these models, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.


Subject(s)
Cell Cycle Proteins/genetics , Gene Expression , Granulocyte-Macrophage Progenitor Cells/metabolism , Granulocytes/metabolism , Macrophages/metabolism , Membrane Proteins/genetics , Monocytes/metabolism , Animals , Granulocyte-Macrophage Progenitor Cells/cytology , Granulocytes/cytology , Hematopoiesis/physiology , Homeostasis/physiology , Inflammation/metabolism , Macrophages/cytology , Mice , Monocytes/cytology
15.
Immunity ; 57(8): 1878-1892.e5, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39043185

ABSTRACT

Lung-tissue-resident memory (TRM) CD8+ T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How TRM cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung TRM cells before and after recall infection. CD69+CD103+ TRM cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung TRM cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific TRM cells revealed the expression of several factors that regulate myeloid cell biology. In vivo rechallenge experiments demonstrated that protection elicited by TRM cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103+ lung TRM cells that mediate early protective immunity against IAV infection.


Subject(s)
Antigens, CD , CD8-Positive T-Lymphocytes , Immunologic Memory , Influenza A virus , Integrin alpha Chains , Lung , Memory T Cells , Orthomyxoviridae Infections , Animals , Lung/immunology , Lung/virology , Orthomyxoviridae Infections/immunology , CD8-Positive T-Lymphocytes/immunology , Mice , Immunologic Memory/immunology , Integrin alpha Chains/metabolism , Influenza A virus/immunology , Antigens, CD/metabolism , Memory T Cells/immunology , Mice, Inbred C57BL , Interferon-gamma/metabolism , Interferon-gamma/immunology , Intravital Microscopy , Monocytes/immunology
16.
Immunity ; 57(9): 2202-2215.e6, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39043184

ABSTRACT

The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.


Subject(s)
Basic-Leucine Zipper Transcription Factors , CD8-Positive T-Lymphocytes , Cell Differentiation , Epigenesis, Genetic , Epigenomics , Immunologic Memory , Memory T Cells , Animals , Cell Differentiation/immunology , Cell Differentiation/genetics , Mice , Memory T Cells/immunology , Memory T Cells/metabolism , Immunologic Memory/genetics , Immunologic Memory/immunology , CD8-Positive T-Lymphocytes/immunology , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Epigenomics/methods , Mice, Inbred C57BL , Organ Specificity/genetics , Organ Specificity/immunology , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-fos/genetics , Transcriptome , Chromatin/metabolism
17.
Immunity ; 57(1): 124-140.e7, 2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38157853

ABSTRACT

Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.


Subject(s)
Coinfection , Humans , Killer Cells, Natural/metabolism , Cell Differentiation
18.
Immunity ; 57(7): 1629-1647.e8, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38754432

ABSTRACT

The pancreatic islet microenvironment is highly oxidative, rendering ß cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.


Subject(s)
Autoimmunity , CD8-Positive T-Lymphocytes , Cell Differentiation , Chemokine CXCL16 , Diabetes Mellitus, Type 1 , Islets of Langerhans , Lipoproteins, LDL , Macrophages , Mice, Inbred NOD , Mice, Knockout , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Mice , Lipoproteins, LDL/metabolism , Lipoproteins, LDL/immunology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Chemokine CXCL16/metabolism , Macrophages/immunology , Macrophages/metabolism , Islets of Langerhans/immunology , Islets of Langerhans/metabolism , Mice, Inbred C57BL
19.
Immunity ; 56(6): 1168-1186, 2023 06 13.
Article in English | MEDLINE | ID: mdl-37315533

ABSTRACT

Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.


Subject(s)
Adipose Tissue , Gastrointestinal Tract , Humans , Inflammation , Liver
20.
Immunity ; 56(8): 1894-1909.e5, 2023 08 08.
Article in English | MEDLINE | ID: mdl-37421943

ABSTRACT

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.


Subject(s)
Lymphoid Tissue , Memory T Cells , Child , Humans , Infant , CD8-Positive T-Lymphocytes , Immunologic Memory , Lymphoid Tissue/metabolism , Mucous Membrane , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Infant, Newborn , Child, Preschool
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