ABSTRACT
The discovery of CD4+ T cell subset-defining master transcription factors and framing of the Th1/Th2 paradigm ignited the CD4+ T cell field. Advances in in vivo experimental systems, however, have revealed that more complex lineage-defining transcriptional networks direct CD4+ T cell differentiation in the lymphoid organs and tissues. This review focuses on the layers of fate decisions that inform CD4+ T cell differentiation in vivo. Cytokine production by antigen-presenting cells and other innate cells influences the CD4+ T cell effector program [e.g., T helper type 1 (Th1), Th2, Th17]. Signals downstream of the T cell receptor influence whether individual clones bearing hallmarks of this effector program become T follicular helper cells, supporting development of B cells expressing specific antibody isotypes, or T effector cells, which activate microbicidal innate cells in tissues. These bifurcated, parallel axes allow CD4+ T cells to augment their particular effector program and prevent disease.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/cytology , Cell Differentiation/genetics , Cytokines/metabolism , Humans , Lymphocyte Activation/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolismABSTRACT
The complement system is an evolutionarily ancient key component of innate immunity required for the detection and removal of invading pathogens. It was discovered more than 100 years ago and was originally defined as a liver-derived, blood-circulating sentinel system that classically mediates the opsonization and lytic killing of dangerous microbes and the initiation of the general inflammatory reaction. More recently, complement has also emerged as a critical player in adaptive immunity via its ability to instruct both B and T cell responses. In particular, work on the impact of complement on T cell responses led to the surprising discoveries that the complement system also functions within cells and is involved in regulating basic cellular processes, predominantly those of metabolic nature. Here, we review current knowledge about complement's role in T cell biology, with a focus on the novel intracellular and noncanonical activities of this ancient system.
Subject(s)
Complement System Proteins/immunology , Immunomodulation , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Adaptive Immunity , Animals , Autoimmunity , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Complement Activation/immunology , Energy Metabolism , Host-Pathogen Interactions/immunology , Humans , Immunity, Cellular , Membrane Cofactor Protein/metabolism , Th1 Cells/immunology , Th1 Cells/metabolismABSTRACT
Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Chemotaxis, Leukocyte , Lymphocytes, Tumor-Infiltrating/metabolism , RGS Proteins/metabolism , T-Lymphocyte Subsets/metabolism , Animals , Apoptosis , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/immunology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ductal, Breast/therapy , Cell Line, Tumor , Chemokines/metabolism , Coculture Techniques , Cytotoxicity, Immunologic , Female , Humans , Immunotherapy, Adoptive , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/transplantation , Mice, Inbred BALB C , Mice, Inbred C57BL , Microscopy, Fluorescence , Microscopy, Video , RGS Proteins/genetics , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/transplantation , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Time Factors , Time-Lapse Imaging , Tumor Cells, Cultured , Tumor EscapeABSTRACT
Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4-TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.
Subject(s)
B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/pharmacology , Lymphocyte Activation/drug effects , Lymphocytic Choriomeningitis/drug therapy , Lymphocytic choriomeningitis virus/immunology , Th1 Cells/drug effects , Adoptive Transfer , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Cell Proliferation/drug effects , Chronic Disease , Cytokines/metabolism , Cytotoxicity, Immunologic/drug effects , Disease Models, Animal , Female , Gene Regulatory Networks , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/metabolism , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/pathogenicity , Mice, Inbred C57BL , Phenotype , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Signal Transduction , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/virology , TranscriptomeABSTRACT
Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.
Subject(s)
Cystitis/etiology , Cystitis/metabolism , Lymphocyte Activation/immunology , Mucous Membrane/immunology , Mucous Membrane/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Animals , Bacterial Load , Biomarkers , Cell Line , Cystitis/pathology , Cytokines/metabolism , Disease Models, Animal , Female , Mice , Mice, Knockout , Mucous Membrane/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/pathology , Urinary Tract Infections/etiology , Urinary Tract Infections/metabolism , Urinary Tract Infections/microbiology , Wound Healing/genetics , Wound Healing/immunologyABSTRACT
Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct-STL provoked profound changes in the intestinal immune system, including induction of an IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In contrast, deficiency in cDC1s skewed the Ct-STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct-STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct-STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection.
Subject(s)
Cryptosporidiosis/immunology , Cryptosporidiosis/parasitology , Cryptosporidium/immunology , Dendritic Cells/immunology , Host-Parasite Interactions/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/parasitology , Th1 Cells/immunology , Animals , Dendritic Cells/metabolism , Disease Models, Animal , Homeostasis , Intestinal Mucosa/metabolism , Mice , Microbiota , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Th1 Cells/metabolismABSTRACT
Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4+ Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4+ T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Fetus/immunology , Immunologic Memory/immunology , Intestines/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , CD4-Positive T-Lymphocytes/metabolism , Epithelial Cells/cytology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Female , Fetus/metabolism , Humans , Infant, Newborn , Intestinal Mucosa/embryology , Intestinal Mucosa/growth & development , Intestinal Mucosa/immunology , Intestines/embryology , Intestines/growth & development , Mice, Inbred C57BL , Pregnancy , Stem Cells/cytology , Stem Cells/immunology , Stem Cells/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Salmonella enterica (Se) bacteria cause persistent intracellular infections while stimulating a robust interferon-γ-producing CD4+ T (Th1) cell response. We addressed this paradox of concomitant infection and immunity by tracking fluorescent Se organisms in mice. Se bacteria persisted in nitric oxide synthase (iNOS)-producing resident and recruited macrophages while inducing genes related to protection from nitric oxide. Se-infected cells occupied iNOS+ splenic granulomas that excluded T cells but were surrounded by mononuclear phagocytes producing the chemokines CXCL9 and CXCL10, and Se epitope-specific Th1 cells expressing CXCR3, the receptor for these chemokines. Blockade of CXCR3 inhibited Th1 occupancy of CXCL9/10-dense regions, reduced activation of the Th1 cells, and led to increased Se growth. Thus, intracellular Se bacteria survive in their hosts by counteracting toxic products of the innate immune response and by residing in T cell-sparse granulomas, away from abundant Th1 cells positioned via CXCR3 in a bordering region that act to limit infection.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Granuloma/immunology , Receptors, CXCR3/immunology , Salmonella Infections/immunology , Salmonella enterica/immunology , Th1 Cells/immunology , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/microbiology , Chemokine CXCL10/immunology , Chemokine CXCL10/metabolism , Chemokine CXCL9/immunology , Chemokine CXCL9/metabolism , Granuloma/metabolism , Granuloma/microbiology , Host-Pathogen Interactions/immunology , Ligands , Macrophage Activation/immunology , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Receptors, CXCR3/metabolism , Salmonella Infections/metabolism , Salmonella Infections/microbiology , Salmonella enterica/physiology , Th1 Cells/metabolism , Th1 Cells/microbiologyABSTRACT
The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin-17 (IL-17)-producing T helper 17 (Th17) cells. Here, we demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T-cell- and Th17-cell-specific deletion of Fas were protected from induced autoimmunity, and Th17 cell differentiation and stability were impaired. Fas-deficient Th17 cells instead developed a Th1-cell-like transcriptional profile, which a new algorithm predicted to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1, and Fas deficiency enhanced IL-6-induced STAT1 activation and nuclear translocation, whereas deficiency of STAT1 reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of opposing STAT1 and STAT3 to have a direct impact on autoimmunity.
Subject(s)
Cell Differentiation/immunology , STAT1 Transcription Factor/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , fas Receptor/metabolism , Animals , Apoptosis/immunology , Biomarkers , Caspases/metabolism , Gene Expression Profiling , Gene Knockout Techniques , Lymphocyte Activation , Mice , Phenotype , Phosphorylation , Protein Binding , Protein Transport , STAT3 Transcription Factor/metabolism , Th17 Cells/cytology , Transcriptome , fas Receptor/geneticsABSTRACT
Appropriate immune responses require a fine balance between immune activation and attenuation. NLRC3, a non-inflammasome-forming member of the NLR innate immune receptor family, attenuates inflammation in myeloid cells and proliferation in epithelial cells. T lymphocytes express the highest amounts of Nlrc3 transcript where its physiologic relevance is unknown. We show that NLRC3 attenuated interferon-γ and TNF expression by CD4+ T cells and reduced T helper 1 (Th1) and Th17 cell proliferation. Nlrc3-/- mice exhibited increased and prolonged CD4+ T cell responses to lymphocytic choriomeningitis virus infection and worsened experimental autoimmune encephalomyelitis (EAE). These functions of NLRC3 were executed in a T-cell-intrinsic fashion: NLRC3 reduced K63-linked ubiquitination of TNF-receptor-associated factor 6 (TRAF6) to limit NF-κB activation, lowered phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and diminished glycolysis and oxidative phosphorylation. This study reveals an unappreciated role for NLRC3 in attenuating CD4+ T cell signaling and metabolism.
Subject(s)
Autoimmunity/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunity, Innate/immunology , Intercellular Signaling Peptides and Proteins/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/immunology , Adaptor Proteins, Signal Transducing , Animals , Autoimmunity/genetics , Carrier Proteins/genetics , Carrier Proteins/immunology , Carrier Proteins/metabolism , Cell Cycle Proteins , Encephalomyelitis, Autoimmune, Experimental/genetics , Eukaryotic Initiation Factors , Humans , Immunity, Innate/genetics , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Lymphocytic Choriomeningitis/genetics , Lymphocytic Choriomeningitis/microbiology , Lymphocytic choriomeningitis virus/physiology , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/immunology , NF-kappa B/metabolism , Phosphoproteins/genetics , Phosphoproteins/immunology , Phosphoproteins/metabolism , TNF Receptor-Associated Factor 6/genetics , TNF Receptor-Associated Factor 6/immunology , TNF Receptor-Associated Factor 6/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolismABSTRACT
The protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor recently emerged as a key regulator of host immunity to infections, autoimmune diseases and cancer. In this study, we investigated the role of Bhlhe40 in protective T cell responses to the intracellular bacterium Chlamydia in the female reproductive tract (FRT). Mice deficient in Bhlhe40 exhibited severe defects in their ability to control Chlamydia muridarum shedding from the FRT. The heightened bacterial burdens in Bhlhe40-/- mice correlated with a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased polyfunctional CD4 T cells co-producing IFN-γ, IL-17A and GM-CSF. Genetic ablation of IL-10 or functional blockade of IL-10R increased CD4 T cell polyfunctionality and partially rescued the defects in bacterial control in Bhlhe40-/- mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures in Bhlhe40-deficient CD4 T cells, whereas WT CD4 T cells were further down on the differentiation trajectory with distinct effector functions beyond IFN-γ production by Th1 cells. Altogether, we identified Bhlhe40 as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT against Chlamydia.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , CD4-Positive T-Lymphocytes , Chlamydia Infections , Chlamydia muridarum , Homeodomain Proteins , Animals , Female , Mice , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation , Chlamydia Infections/immunology , Chlamydia muridarum/physiology , Interleukin-10/metabolism , Mice, Inbred C57BL , Th1 Cells/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Homeodomain Proteins/metabolismABSTRACT
The transcription factor ThPOK promotes CD4(+) T cell differentiation in the thymus. Here, using a mouse strain that allows post-thymic gene deletion, we show that ThPOK maintains CD4(+) T lineage integrity and couples effector differentiation to environmental cues after antigenic stimulation. ThPOK preserved the integrity and amplitude of effector responses and was required for proper differentiation of types 1 and 2 helper T cells in vivo by restraining the expression and function of Runx3, a nuclear factor crucial for cytotoxic T cell differentiation. The transcription factor LRF acts redundantly with ThPOK to prevent the transdifferentiation of mature CD4(+) T cells into CD8(+) T cells. As such, the ThPOK-LRF transcriptional module was essential for CD4(+) T cell integrity and responses.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , DNA-Binding Proteins/immunology , Thymus Gland/immunology , Transcription Factors/immunology , Animals , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/immunology , Cell Lineage/genetics , Cell Lineage/immunology , Core Binding Factor Alpha 3 Subunit/genetics , Core Binding Factor Alpha 3 Subunit/immunology , Core Binding Factor Alpha 3 Subunit/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Flow Cytometry , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Thymus Gland/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transcriptome/immunologyABSTRACT
Leukocytes must traverse inflamed tissues to effectively control local infection. Although motility in dense tissues seems to be integrin independent and based on actomyosin-mediated protrusion and contraction, during inflammation, changes to the extracellular matrix (ECM) may necessitate distinct motility requirements. Indeed, we found that the interstitial motility of T cells was critically dependent on Arg-Gly-Asp (RGD)-binding integrins in the inflamed dermis. Inflammation-induced deposition of fibronectin was functionally linked to higher expression of integrin αV on effector CD4⺠T cells. By intravital multiphoton imaging, we found that the motility of CD4⺠T cells was dependent on αV expression. Selective blockade or knockdown of αV arrested T helper type 1 (TH1) cells in the inflamed tissue and attenuated local effector function. Our data demonstrate context-dependent specificity of lymphocyte movement in inflamed tissues that is essential for protective immunity.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Movement/immunology , Inflammation/immunology , Inflammation/metabolism , Integrin alphaV/metabolism , Animals , Dermis/immunology , Dermis/metabolism , Extracellular Matrix/metabolism , Gene Expression Regulation , Inflammation/genetics , Integrin alphaV/genetics , Lymph Nodes/immunology , Mice , Oligopeptides/metabolism , Protein Binding , Th1 Cells/immunology , Th1 Cells/metabolismABSTRACT
Two distinct subsets of γδ T cells that produce interleukin 17 (IL-17) (CD27(-) γδ T cells) or interferon-γ (IFN-γ) (CD27(+) γδ T cells) develop in the mouse thymus, but the molecular determinants of their functional potential in the periphery remain unknown. Here we conducted a genome-wide characterization of the methylation patterns of histone H3, along with analysis of mRNA encoding transcription factors, to identify the regulatory networks of peripheral IFN-γ-producing or IL-17-producing γδ T cell subsets in vivo. We found that CD27(+) γδ T cells were committed to the expression of Ifng but not Il17, whereas CD27(-) γδ T cells displayed permissive chromatin configurations at loci encoding both cytokines and their regulatory transcription factors and differentiated into cells that produced both IL-17 and IFN-γ in a tumor microenvironment.
Subject(s)
Cell Differentiation/genetics , Epigenesis, Genetic , Gene Expression Profiling , Receptors, Antigen, T-Cell, gamma-delta/genetics , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolism , Transcriptome , Animals , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Regulation , Genome-Wide Association Study , Histones/metabolism , Methylation , Mice , Mice, Knockout , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocyte Subsets/immunology , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolismABSTRACT
Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling. Recently identified ILC populations have a cytokine expression pattern that resembles that of the helper T cell subsets T(H)2, T(H)17 and T(H)22. Here we describe a distinct ILC subset similar to T(H)1 cells, which we call 'ILC1'. ILC1 cells expressed the transcription factor T-bet and responded to interleukin 12 (IL-12) by producing interferon-γ (IFN-γ). ILC1 cells were distinct from natural killer (NK) cells as they lacked perforin, granzyme B and the NK cell markers CD56, CD16 and CD94, and could develop from RORγt(+) ILC3 under the influence of IL-12. The frequency of the ILC1 subset was much higher in inflamed intestine of people with Crohn's disease, which indicated a role for these IFN-γ-producing ILC1 cells in the pathogenesis of gut mucosal inflammation.
Subject(s)
Crohn Disease/immunology , Interleukin-12/metabolism , Intestinal Mucosa/immunology , Lymphocyte Subsets/immunology , Lymphocytes/immunology , T-Box Domain Proteins/biosynthesis , Animals , CD56 Antigen/analysis , Cell Differentiation , Cells, Cultured , Colitis/immunology , Cytokines/immunology , Cytokines/metabolism , Granzymes/analysis , Humans , Inflammation , Interferon-gamma/biosynthesis , Intestinal Mucosa/metabolism , Intestines/immunology , Killer Cells, Natural/immunology , Lymphocyte Subsets/metabolism , Lymphocytes/metabolism , Mice , NK Cell Lectin-Like Receptor Subfamily D/analysis , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Perforin/analysis , Receptors, IgG/analysis , Th1 Cells/immunology , Th1 Cells/metabolismABSTRACT
Although intergenic long noncoding RNAs (lincRNAs) have been linked to gene regulation in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identified 1,524 lincRNA clusters in 42 T cell samples, from early T cell progenitors to terminally differentiated helper T cell subsets. Our analysis revealed highly dynamic and cell-specific expression patterns for lincRNAs during T cell differentiation. These lincRNAs were located in genomic regions enriched for genes that encode proteins with immunoregulatory functions. Many were bound and regulated by the key transcription factors T-bet, GATA-3, STAT4 and STAT6. We found that the lincRNA LincR-Ccr2-5'AS, together with GATA-3, was an essential component of a regulatory circuit in gene expression specific to the TH2 subset of helper T cells and was important for the migration of TH2 cells.
Subject(s)
Gene Expression Regulation/immunology , Precursor Cells, T-Lymphoid/metabolism , RNA, Long Noncoding/genetics , Th1 Cells/metabolism , Th17 Cells/metabolism , Th2 Cells/metabolism , Animals , Cell Differentiation , Cell Movement , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/immunology , GATA3 Transcription Factor/metabolism , Genetic Loci , Mice , Mice, Inbred C57BL , Molecular Sequence Annotation , Precursor Cells, T-Lymphoid/cytology , Precursor Cells, T-Lymphoid/immunology , Protein Binding , RNA, Long Noncoding/immunology , STAT4 Transcription Factor/genetics , STAT4 Transcription Factor/immunology , STAT4 Transcription Factor/metabolism , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/immunology , STAT6 Transcription Factor/metabolism , Signal Transduction , T-Box Domain Proteins/genetics , T-Box Domain Proteins/immunology , T-Box Domain Proteins/metabolism , Th1 Cells/cytology , Th1 Cells/immunology , Th17 Cells/cytology , Th17 Cells/immunology , Th2 Cells/cytology , Th2 Cells/immunology , Transcriptome/immunologyABSTRACT
The transcription factor Foxo3 plays a crucial role in myeloid cell function but its role in lymphoid cells remains poorly defined. Here, we have shown that Foxo3 expression was increased after T cell receptor engagement and played a specific role in the polarization of CD4+ T cells toward pathogenic T helper 1 (Th1) cells producing interferon-γ (IFN-γ) and granulocyte monocyte colony stimulating factor (GM-CSF). Consequently, Foxo3-deficient mice exhibited reduced susceptibility to experimental autoimmune encephalomyelitis. At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+ T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+ T cells restored both IFN-γ and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.
Subject(s)
Cell Differentiation/physiology , Forkhead Box Protein O3/metabolism , Interleukin-1/metabolism , T-Box Domain Proteins/metabolism , Th1 Cells/metabolism , Th1 Cells/pathology , Transcription Factors/metabolism , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Cell Differentiation/immunology , Cell Line , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Forkhead Box Protein O3/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , HEK293 Cells , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-1/immunology , Male , Mice , Mice, Inbred C57BL , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , T-Box Domain Proteins/immunology , Th1 Cells/immunologyABSTRACT
Multiple sclerosis (MS) is a highly prevalent demyelinating autoimmune condition; the mechanisms regulating its severity and progression are unclear. The IL-17-producing Th17 subset of T cells has been widely implicated in MS and in the mouse model, experimental autoimmune encephalomyelitis (EAE). However, the differentiation and regulation of Th17 cells during EAE remain incompletely understood. Although evidence is mounting that the antimicrobial peptide cathelicidin profoundly affects early T cell differentiation, no studies have looked at its role in longer-term T cell responses. Now, we report that cathelicidin drives severe EAE disease. It is released from neutrophils, microglia, and endothelial cells throughout disease; its interaction with T cells potentiates Th17 differentiation in lymph nodes and Th17 to exTh17 plasticity and IFN-γ production in the spinal cord. As a consequence, mice lacking cathelicidin are protected from severe EAE. In addition, we show that cathelicidin is produced by the same cell types in the active brain lesions in human MS disease. We propose that cathelicidin exposure results in highly activated, cytokine-producing T cells, which drive autoimmunity; this is a mechanism through which neutrophils amplify inflammation in the central nervous system.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Antimicrobial Cationic Peptides , Antimicrobial Peptides , Cell Differentiation , Encephalomyelitis, Autoimmune, Experimental/pathology , Endothelial Cells/metabolism , Humans , Mice , Mice, Inbred C57BL , Th1 Cells/metabolism , Th1 Cells/pathology , Th17 Cells/metabolism , CathelicidinsABSTRACT
Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6+ cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to yield the unusual plasticity ascribed to type 17 cells.
Subject(s)
Autoimmune Diseases , Th17 Cells , Humans , Cell Differentiation , Phenotype , Receptors, CCR6/genetics , Th1 Cells/metabolismABSTRACT
IL-6 plays a fundamental role in T cell differentiation and is strictly controlled by surface expression and shedding of IL-6R. IL-6 also acts on other cells that might affect T cell maturation. To study the impact of cell-autonomous and uncontrolled IL-6 signaling in T cells, we generated mice with a constitutively active IL-6R gp130 chain (Lgp130) expressed either in all T cells (Lgp130 × CD4Cre mice) or inducible in CD4+ T cells (Lgp130 × CD4CreERT2 mice). Lgp130 × CD4Cre mice accumulated activated T cells, including TH17 cells, in the lung, resulting in severe inflammation. Tamoxifen treatment of Lgp130 × CD4CreERT2 mice caused Lgp130 expression in 40-50% of CD4+ T cells, but mice developed lung disease only after several months. Lgp130+ CD4+ T cells were also enriched for TH17 cells; however, there was concomitant expansion of Lgp130- regulatory T cells, which likely restricted pathologic Lgp130+ T cells. In vitro, constitutive gp130 signaling in T cells enhanced but was not sufficient for TH17 cell differentiation. Augmented TH17 cell development of Lgp130+ T cells was also observed in Lgp130 × CD4CreERT2 mice infected with Staphylococcus aureus, but gp130 activation did not interfere with formation of TH1 cells against Listeria monocytogenes. Lgp130+ CD4+ T cells acquired a memory T cell phenotype and persisted in high numbers as a polyclonal T cell population in lymphoid and peripheral tissues, but we did not observe T cell lymphoma formation. In conclusion, cell-autonomous gp130 signaling alters T cell differentiation. Although gp130 signaling is not sufficient for TH17 cell differentiation, it still promotes accumulation of activated T cells in the lung that cause tissue inflammation.