RESUMO
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.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/genética , Citocinas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly. Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen.
Assuntos
Antineoplásicos , Infecções por Citomegalovirus , Humanos , Idoso , Citomegalovirus , Linfócitos T Citotóxicos , Antígenos HLA , Linfócitos T CD4-Positivos , Senescência CelularRESUMO
CD4+ T cells play fundamental roles in orchestrating immune responses and tissue homeostasis. However, our inability to associate peptide human leukocyte antigen class-II (HLA-II) complexes with their cognate T cell receptors (TCRs) in an unbiased manner has hampered our understanding of CD4+ T cell function and role in pathologies. Here, we introduce TScan-II, a highly sensitive genome-scale CD4+ antigen discovery platform. This platform seamlessly integrates the endogenous HLA-II antigen-processing machinery in synthetic antigen-presenting cells and TCR signaling in T cells, enabling the simultaneous screening of multiple HLAs and TCRs. Leveraging genome-scale human, virome, and epitope mutagenesis libraries, TScan-II facilitates de novo antigen discovery and deep exploration of TCR specificity. We demonstrate TScan-II's potential for basic and translational research by identifying a non-canonical antigen for a cancer-reactive CD4+ T cell clone. Additionally, we identified two antigens for clonally expanded CD4+ T cells in Sjögren's disease, which bind distinct HLAs and are expressed in HLA-II-positive ductal cells within affected salivary glands.
Assuntos
Linfócitos T CD4-Positivos , Epitopos de Linfócito T , Humanos , Células Apresentadoras de Antígenos , Antígenos CD4/metabolismo , Antígenos HLA/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linhagem Celular , Genoma HumanoRESUMO
SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.
Assuntos
COVID-19/imunologia , COVID-19/virologia , Imunidade/imunologia , SARS-CoV-2/imunologia , Células T Auxiliares Foliculares/imunologia , Vacinação , Vacinas Sintéticas/imunologia , Vacinas de mRNA/imunologia , Adulto , Linfócitos B/imunologia , Vacina BNT162/imunologia , COVID-19/sangue , Células Clonais , Estudos de Coortes , Citocinas/metabolismo , Feminino , Centro Germinativo/imunologia , Cadeias beta de HLA-DP/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Células Jurkat , Linfonodos/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/metabolismo , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.
Assuntos
Doença Enxerto-Hospedeiro , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/microbiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T CD4-Positivos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Microbiota/imunologia , Seleção Clonal Mediada por Antígeno , Transplante Homólogo , Teorema de Bayes , Transplante de Células-Tronco/efeitos adversos , Camundongos Endogâmicos BALB C , Microbioma Gastrointestinal/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Linfócitos T CD8-Positivos , Infecções Irruptivas , RNA Viral , Anticorpos Neutralizantes , Anticorpos Antivirais , VacinaçãoRESUMO
The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.
Assuntos
Glioblastoma , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Antígeno CTLA-4 , Células Th1 , Microglia , Linfócitos T CD8-Positivos , Fagocitose , Células Dendríticas , Linfócitos T CD4-PositivosRESUMO
T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.
Assuntos
COVID-19 , Vacinas , Humanos , Linfócitos T CD8-Positivos , Vacina BNT162 , SARS-CoV-2 , Vacinação , Anticorpos AntiviraisRESUMO
Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.
Assuntos
COVID-19 , Vacinas Virais , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , SARS-CoV-2 , VacinaçãoRESUMO
Allergic airway inflammation is driven by type-2 CD4+ T cell inflammatory responses. We uncover an immunoregulatory role for the nucleotide release channel, Panx1, in T cell crosstalk during airway disease. Inverse correlations between Panx1 and asthmatics and our mouse models revealed the necessity, specificity, and sufficiency of Panx1 in T cells to restrict inflammation. Global Panx1-/- mice experienced exacerbated airway inflammation, and T-cell-specific deletion phenocopied Panx1-/- mice. A transgenic designed to re-express Panx1 in T cells reversed disease severity in global Panx1-/- mice. Panx1 activation occurred in pro-inflammatory T effector (Teff) and inhibitory T regulatory (Treg) cells and mediated the extracellular-nucleotide-based Treg-Teff crosstalk required for suppression of Teff cell proliferation. Mechanistic studies identified a Salt-inducible kinase-dependent phosphorylation of Panx1 serine 205 important for channel activation. A genetically targeted mouse expressing non-phosphorylatable Panx1S205A phenocopied the exacerbated inflammation in Panx1-/- mice. These data identify Panx1-dependent Treg:Teff cell communication in restricting airway disease.
Assuntos
Asma/imunologia , Comunicação Celular/imunologia , Conexinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Conexinas/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Células Jurkat , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Sistema Respiratório/imunologiaRESUMO
Appropriate balance of T helper 17 (Th17) and regulatory T (Treg) cells maintains immune tolerance and host defense. Disruption of Th17-Treg cell balance is implicated in a number of immune-mediated diseases, many of which display dysregulation of the insulin-like growth factor (IGF) system. Here, we show that, among effector T cell subsets, Th17 and Treg cells selectively expressed multiple components of the IGF system. Signaling through IGF receptor (IGF1R) activated the protein kinase B-mammalian target of rapamycin (AKT-mTOR) pathway, increased aerobic glycolysis, favored Th17 cell differentiation over that of Treg cells, and promoted a heightened pro-inflammatory gene expression signature. Group 3 innate lymphoid cells (ILC3s), but not ILC1s or ILC2s, were similarly responsive to IGF signaling. Mice with deficiency of IGF1R targeted to T cells failed to fully develop disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Thus, the IGF system represents a previously unappreciated pathway by which type 3 immunity is modulated and immune-mediated pathogenesis controlled.
Assuntos
Autoimunidade , Encefalomielite Autoimune Experimental/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptor IGF Tipo 1/imunologia , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/imunologia , Células Th17/imunologia , Animais , Comunicação Celular , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica , Tolerância Imunológica , Imunidade Inata , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Receptor IGF Tipo 1/genética , Transdução de Sinais , Linfócitos T Reguladores/patologia , Serina-Treonina Quinases TOR/genética , Células Th17/patologiaRESUMO
Memory CD4+ T cells mediate long-term immunity, and their generation is a key objective of vaccination strategies. However, the transcriptional circuitry controlling the emergence of memory cells from early CD4+ antigen-responders remains poorly understood. Here, using single-cell RNA-seq to study the transcriptome of virus-specific CD4+ T cells, we identified a gene signature that distinguishes potential memory precursors from effector cells. We found that both that signature and the emergence of memory CD4+ T cells required the transcription factor Thpok. We further demonstrated that Thpok cell-intrinsically protected memory cells from a dysfunctional, effector-like transcriptional program, similar to but distinct from the exhaustion pattern of cells responding to chronic infection. Mechanistically, Thpok- bound genes encoding the transcription factors Blimp1 and Runx3 and acted by antagonizing their expression. Thus, a Thpok-dependent circuitry promotes both memory CD4+ T cells' differentiation and functional fitness, two previously unconnected critical attributes of adaptive immunity.
Assuntos
Linfócitos T CD4-Positivos/fisiologia , Subpopulações de Linfócitos T/fisiologia , Fatores de Transcrição/metabolismo , Animais , Antígenos Virais/imunologia , Diferenciação Celular , Células Cultivadas , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Humanos , Memória Imunológica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Ligação Proteica , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Transcrição/genética , TranscriptomaRESUMO
Although CD4+ T cell "help" is crucial to sustain antiviral immunity, the mechanisms by which CD4+ T cells regulate CD8+ T cell differentiation during chronic infection remain elusive. Here, using single-cell RNA sequencing, we show that CD8+ T cells responding to chronic infection were more heterogeneous than previously appreciated. Importantly, our findings uncovered the formation of a CX3CR1-expressing CD8+ T cell subset that exhibited potent cytolytic function and was required for viral control. Notably, our data further demonstrate that formation of this cytotoxic subset was critically dependent on CD4+ T cell help via interleukin-21 (IL-21) and that exploitation of this developmental pathway could be used therapeutically to enhance the killer function of CD8+ T cells infiltrated into the tumor. These findings uncover additional molecular mechanisms of how "CD4+ T cell help" regulates CD8+ T cell differentiation during persistent infection and have implications toward optimizing the generation of protective CD8+ T cells in immunotherapy.
Assuntos
Infecções , Neoplasias , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Receptor de Morte Celular Programada 1 , Subpopulações de Linfócitos TRESUMO
CD4+ T cells are crucial in generating and sustaining immune responses. They orchestrate and fine-tune mammalian innate and adaptive immunity through cell-based interactions and the release of cytokines. The role of these cells in contributing to the efficacy of antitumor immunity and immunotherapy has just started to be uncovered. Yet, many aspects of the CD4+ T cell response are still unclear, including the differentiation pathways controlling such cells during cancer progression, the external signals that program them, and how the combination of these factors direct ensuing immune responses or immune-restorative therapies. In this review, we focus on recent advances in understanding CD4+ T cell regulation during cancer progression and the importance of CD4+ T cells in immunotherapies.
Assuntos
Neoplasias , Linfócitos T , Animais , Humanos , Linfócitos T/patologia , Imunoterapia , Imunidade Adaptativa , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , MamíferosRESUMO
CD8+ T cell exhaustion impedes control of chronic viral infection; yet how new T cell responses are mounted during chronic infection is unclear. Unlike T cells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8+ T cells primed after establishment of chronic LCMV infection preferentially generate memory-like transcription factor TCF1+ cells that were transcriptionally and proteomically distinct, less exhausted, and more responsive to immunotherapy. Mechanistically, adaptations of antigen-presenting cells and diminished T cell signaling intensity promoted differentiation of the memory-like subset at the expense of rapid effector cell differentiation, which was now highly dependent on IL-21-mediated CD4+ T cell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8+ T cells, ultimately preventing cancer control. Thus, targeting these T cell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Imunidade/imunologia , Memória Imunológica/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/virologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/genética , Doença Crônica , Perfilação da Expressão Gênica/métodos , Imunidade/genética , Memória Imunológica/genética , Imunoterapia , Coriomeningite Linfocítica/terapia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Proteômica/métodos , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/imunologia , Fator 1 de Transcrição de Linfócitos T/metabolismoRESUMO
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.
Assuntos
Autoimunidade/imunologia , Encefalomielite Autoimune Experimental/imunologia , Imunidade Inata/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Autoimunidade/genética , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Encefalomielite Autoimune Experimental/genética , Fatores de Iniciação em Eucariotos , Humanos , Imunidade Inata/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/microbiologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/imunologia , NF-kappa B/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/imunologia , Fator 6 Associado a Receptor de TNF/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Pulmonary arterial hypertension (PAH) is characterized by stenosis and occlusions of small pulmonary arteries, leading to elevated pulmonary arterial pressure and right heart failure. Although accumulating evidence shows the importance of interleukin (IL)-6 in the pathogenesis of PAH, the target cells of IL-6 are poorly understood. Using mice harboring the floxed allele of gp130, a subunit of the IL-6 receptor, we found substantial Cre recombination in all hematopoietic cell lineages from the primitive hematopoietic stem cell level in SM22α-Cre mice. We also revealed that a CD4+ cell-specific gp130 deletion ameliorated the phenotype of hypoxia-induced pulmonary hypertension in mice. Disruption of IL-6 signaling via deletion of gp130 in CD4+ T cells inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and suppressed the hypoxia-induced increase in T helper 17 cells. To further examine the role of IL-6/gp130 signaling in more severe PH models, we developed Il6 knockout (KO) rats using the CRISPR/Cas9 system and showed that IL-6 deficiency could improve the pathophysiology in hypoxia-, monocrotaline-, and Sugen5416/hypoxia (SuHx)-induced rat PH models. Phosphorylation of STAT3 in CD4+ cells was also observed around the vascular lesions in the lungs of the SuHx rat model, but not in Il6 KO rats. Blockade of IL-6 signaling had an additive effect on conventional PAH therapeutics, such as endothelin receptor antagonist (macitentan) and soluble guanylyl cyclase stimulator (BAY41-2272). These findings suggest that IL-6/gp130 signaling in CD4+ cells plays a critical role in the pathogenesis of PAH.
Assuntos
Hipertensão Pulmonar , Interleucina-6 , Animais , Camundongos , Ratos , Linfócitos T CD4-Positivos/patologia , Receptor gp130 de Citocina/genética , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Interleucina-6/genética , Artéria Pulmonar/patologiaRESUMO
Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses toward antibody production via Tfh cells or inflammation by Teff cells. Tfh-Teff cell fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6-Blimp-1 counter-antagonism. We found that the TCR-signal-induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells. Increased TCR signaling raised Irf4 amounts and promoted Teff cell fates at the expense of Tfh ones. Importantly, orthogonal induction of Irf4 expression redirected Tfh cell fate trajectories toward those of Teff. Mechanistically, we linked greater Irf4 abundance with its recruitment toward low-affinity binding sites within Teff cell cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the "reader" of TCR signal strength, and in turn, concentration-dependent activity of Irf4 "writes" T helper fate choice.
Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Fatores Reguladores de Interferon/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Antígenos/imunologia , Sítios de Ligação , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Humanos , Imunização , Fatores Reguladores de Interferon/genética , Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Knockout , Motivos de Nucleotídeos , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
CD4+ T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes in CTLs resulting from CD4+ T cell help after anti-cancer vaccination or virus infection. The gene expression signatures revealed that CD4+ T cell help during priming optimized CTLs in expression of cytotoxic effector molecules and many other functions that ensured efficacy of CTLs throughout their life cycle. Key features included downregulation of PD-1 and other coinhibitory receptors that impede CTL activity, and increased motility and migration capacities. "Helped" CTLs acquired chemokine receptors that helped them reach their tumor target tissue and metalloprotease activity that enabled them to invade into tumor tissue. A very large part of the "help" program was instilled in CD8+ T cells via CD27 costimulation. The help program thus enhances specific CTL effector functions in response to vaccination or a virus infection.
Assuntos
Ligante CD27/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T Citotóxicos/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Animais , Receptor 1 de Quimiocina CX3C/fisiologia , Diferenciação Celular , Movimento Celular , Regulação para Baixo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR4/fisiologiaRESUMO
Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.