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The increasing implication of lymphocytes in general physiology and immune surveillance outside of infection poses the question of how their antigen receptors might be involved. Here, we show that macromolecular aggregates of intraepidermal γδ T cell antigen receptors (TCRs) in the mouse skin aligned with and depended on Skint1, a butyrophilin-like (BTNL) protein expressed by differentiated keratinocytes (KCs) at steady state. Interruption of TCR-mediated 'normality sensing' had no impact on γδ T cell numbers but altered their signature phenotype, while the epidermal barrier function was compromised. In addition to the regulation of steady-state physiology, normality sensing licensed intraepidermal T cells to respond rapidly to subsequent tissue perturbation by using innate tumor necrosis factor (TNF) superfamily receptors. Thus, interfering with Skint1-dependent interactions between local γδ T cells and KCs at steady state increased the susceptibility to ultraviolet B radiation (UVR)-induced DNA damage and inflammation, two cancer-disposing factors.
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Linfocitos Intraepiteliales , Receptores de Antígenos de Linfocitos T gamma-delta , Animales , Butirofilinas , Epidermis , Linfocitos Intraepiteliales/metabolismo , Concesión de Licencias , Ratones , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismoRESUMEN
Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) ß and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRß and TCRδ loci, including some TCRß sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.
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Inmunidad Adaptativa , COVID-19 , Cadenas Pesadas de Inmunoglobulina , Receptores de Antígenos de Linfocitos T alfa-beta , Receptores de Antígenos de Linfocitos T , SARS-CoV-2 , Inmunidad Adaptativa/genética , Anciano , Linfocitos B/inmunología , COVID-19/genética , COVID-19/inmunología , Sitios Genéticos , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , SARS-CoV-2/inmunología , Seroconversión , Linfocitos T/inmunologíaRESUMEN
Leukocyte homing driven by the chemokine CCL21 is pivotal for adaptive immunity because it controls dendritic cell (DC) and T cell migration through CCR7. ACKR4 scavenges CCL21 and has been shown to play an essential role in DC trafficking at the steady state and during immune responses to tumors and cutaneous inflammation. However, the mechanism by which ACKR4 regulates peripheral DC migration is unknown, and the extent to which it regulates CCL21 in steady-state skin and lymph nodes (LNs) is contested. Specifically, our previous findings that CCL21 levels are increased in LNs of ACKR4-deficient mice [I. Comerford et al., Blood 116, 4130-4140 (2010)] were refuted [M. H. Ulvmar et al., Nat. Immunol. 15, 623-630 (2014)], and no differences in CCL21 levels in steady-state skin of ACKR4-deficient mice were reported despite compromised CCR7-dependent DC egress in these animals [S. A. Bryce et al., J. Immunol. 196, 3341-3353 (2016)]. Here, we resolve these issues and reveal that two forms of CCL21, full-length immobilized and cleaved soluble CCL21, exist in steady-state barrier tissues, and both are regulated by ACKR4. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes downstream LNs. The results identify the mechanism by which ACKR4 controls DC migration in barrier tissues and reveal a complex mode of CCL21 regulation in vivo, which enhances understanding of functional chemokine gradient formation.
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Movimiento Celular , Quimiocina CCL21/metabolismo , Células Dendríticas/fisiología , Ganglios Linfáticos/metabolismo , Receptores CCR/metabolismo , Animales , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer. METHODS: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021. Participants who were vaccinated between Dec 8 and Dec 29, 2020, received two 30 µg doses of BNT162b2 administered intramuscularly 21 days apart; patients vaccinated after this date received only one 30 µg dose with a planned follow-up boost at 12 weeks. Blood samples were taken before vaccination and at 3 weeks and 5 weeks after the first vaccination. Where possible, serial nasopharyngeal real-time RT-PCR (rRT-PCR) swab tests were done every 10 days or in cases of symptomatic COVID-19. The coprimary endpoints were seroconversion to SARS-CoV-2 spike (S) protein in patients with cancer following the first vaccination with the BNT162b2 vaccine and the effect of vaccine boosting after 21 days on seroconversion. All participants with available data were included in the safety and immunogenicity analyses. Ongoing follow-up is underway for further blood sampling after the delayed (12-week) vaccine boost. This study is registered with the NHS Health Research Authority and Health and Care Research Wales (REC ID 20/HRA/2031). FINDINGS: 151 patients with cancer (95 patients with solid cancer and 56 patients with haematological cancer) and 54 healthy controls were enrolled. For this interim data analysis of the safety and immunogenicity of vaccinated patients with cancer, samples and data obtained up to March 19, 2021, were analysed. After exclusion of 17 patients who had been exposed to SARS-CoV-2 (detected by either antibody seroconversion or a positive rRT-PCR COVID-19 swab test) from the immunogenicity analysis, the proportion of positive anti-S IgG titres at approximately 21 days following a single vaccine inoculum across the three cohorts were 32 (94%; 95% CI 81-98) of 34 healthy controls; 21 (38%; 26-51) of 56 patients with solid cancer, and eight (18%; 10-32) of 44 patients with haematological cancer. 16 healthy controls, 25 patients with solid cancer, and six patients with haematological cancer received a second dose on day 21. Of the patients with available blood samples 2 weeks following a 21-day vaccine boost, and excluding 17 participants with evidence of previous natural SARS-CoV-2 exposure, 18 (95%; 95% CI 75-99) of 19 patients with solid cancer, 12 (100%; 76-100) of 12 healthy controls, and three (60%; 23-88) of five patients with haematological cancers were seropositive, compared with ten (30%; 17-47) of 33, 18 (86%; 65-95) of 21, and four (11%; 4-25) of 36, respectively, who did not receive a boost. The vaccine was well tolerated; no toxicities were reported in 75 (54%) of 140 patients with cancer following the first dose of BNT162b2, and in 22 (71%) of 31 patients with cancer following the second dose. Similarly, no toxicities were reported in 15 (38%) of 40 healthy controls after the first dose and in five (31%) of 16 after the second dose. Injection-site pain within 7 days following the first dose was the most commonly reported local reaction (23 [35%] of 65 patients with cancer; 12 [48%] of 25 healthy controls). No vaccine-related deaths were reported. INTERPRETATION: In patients with cancer, one dose of the BNT162b2 vaccine yields poor efficacy. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose. These data support prioritisation of patients with cancer for an early (day 21) second dose of the BNT162b2 vaccine. FUNDING: King's College London, Cancer Research UK, Wellcome Trust, Rosetrees Trust, and Francis Crick Institute.
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Vacunas contra la COVID-19/uso terapéutico , COVID-19/inmunología , Neoplasias/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Vacuna BNT162 , COVID-19/sangre , COVID-19/complicaciones , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Inmunogenicidad Vacunal/inmunología , Londres/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/complicaciones , Neoplasias/virología , Estudios Prospectivos , SARS-CoV-2 , GalesRESUMEN
Mesenchymal stromal cells or stem cells (MSCs) have been shown to participate in tissue repair and are immunomodulatory in neuropathological settings. Given this, their potential use in developing a new generation of personalized therapies for autoimmune and inflammatory diseases of the central nervous system (CNS) will be explored. To effectively exert these effector functions, MSCs must first gain entry into damaged neural tissues, a process that has been demonstrated to be a limiting factor in their therapeutic efficacy. In this review, we discuss approaches to maximize the therapeutic efficacy of MSCs by altering their intrinsic trafficking programs to effectively enter neuropathological sites. To this end, we explore the significant role of chemokine receptors and adhesion molecules in directing cellular traffic to the inflamed CNS and the capacity of MSCs to adopt these molecular mechanisms to gain entry to this site. We postulate that understanding and exploiting these migratory mechanisms may be key to the development of cell-based therapies tailored to respond to the migratory cues unique to the nature and stage of progression of individual CNS disorders.
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Células Madre Adultas/trasplante , Autoinmunidad , Encéfalo/patología , Inflamación/inmunología , Inflamación/terapia , Células Madre Mesenquimatosas/citología , Humanos , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/terapiaRESUMEN
Differentiation of naïve CD4⺠cells into functionally distinct effector helper T cell subsets, characterised by distinct "cytokine signatures," is a cardinal strategy employed by the mammalian immune system to efficiently deal with the rapidly evolving array of pathogenic microorganisms encountered by the host. Since the T(H)1/T(H)2 paradigm was first described by Mosmann and Coffman, research in the field of helper T cell biology has grown exponentially with seven functionally unique subsets having now been described. In this review, recent insights into the molecular mechanisms that govern differentiation and function of effector helper T cell subsets will be discussed in the context of microbial infections, with a focus on how these different helper T cell subsets orchestrate immune responses tailored to combat the nature of the pathogenic threat encountered.
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Inmunidad Adaptativa/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular/inmunología , Humanos , Subgrupos de Linfocitos T/citología , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
Lymphocyte trafficking is a key step in the pathogenesis of various autoimmune diseases. Recruitment of autoreactive lymphocytes to inflamed tissues is a defining feature of numerous persistent organ-specific autoimmune conditions and various therapies are now used in several of these diseases which appear to specifically block lymphocyte migration. Thus, better understanding of the molecular events involved in homing of autoreactive pathogenic lymphocytes may present novel opportunities for pharmacological intervention in autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, type-1 diabetes and psoriasis. This review describes recent progress in understanding lymphocyte trafficking in autoimmunity, focusing on the involvement of the chemokine and chemokine receptor superfamily. Possible strategies to improve therapeutics for autoimmune diseases arising from these studies are discussed.
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Enfermedades Autoinmunes/inmunología , Quimiocinas/inmunología , Linfocitos/inmunología , Animales , Enfermedades Autoinmunes/patología , Movimiento Celular , Humanos , Inflamación/inmunología , Activación de Linfocitos/inmunología , Linfocitos/patologíaRESUMEN
This study offers longitudinal insight into the impact of three SARS-CoV-2 vaccinations on humoral and cellular immunity in patients with solid cancers, patients with hematologic malignancies, and persons without cancer. For all cohorts, virus-neutralizing immunity was significantly depleted over a period of up to 9 months following the second vaccine dose, the one striking exception being IL2 production by SARS-CoV-2 antigen-specific T cells. Immunity was restored by the third vaccine dose, except in a substantial number of patients with hematologic malignancy, for whom both cancer type and treatment schedule were associated with nonresponse. Thus, whereas most patients with myelodysplastic syndrome were conspicuously good responders, some patients with other hematologic malignancies receiving cancer therapies within 2 weeks of vaccination showed no seroconversion despite three vaccine doses. Moreover, SARS-CoV-2 exposure during the course of the study neither prevented immunity waning, even in healthy controls, nor guaranteed vaccine responsiveness. These data offer real-world human immunologic insights that can inform health policy for patients with cancer.
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COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2/genéticaRESUMEN
Crosstalk between T and B cells is crucial for generating high-affinity, class-switched antibody responses. The roles of CD4+ T cells in this process have been well-characterised. In contrast, regulation of antibody responses by CD8+ T cells is significantly less defined. CD8+ T cells are principally recognised for eliciting cytotoxic responses in peripheral tissues and forming protective memory. However, recent findings have identified a novel population of effector CD8+ T cells that co-opt a differentiation program characteristic of CD4+ T follicular helper (Tfh) cells, upregulate the chemokine receptor CXCR5 and localise to B cell follicles. While it has been shown that CXCR5+CD8+ T cells mediate the removal of viral reservoirs in the context of follicular-trophic viral infections and maintain the response to chronic insults by virtue of progenitor/stem-like properties, it is not known if CXCR5+CD8+ T cells arise during acute peripheral challenges in the absence of follicular infection and whether they influence B cell responses in vivo in these settings. Using the ovalbumin-specific T cell receptor transgenic (OT-I) system in an adoptive transfer-immunisation/infection model, this study demonstrates that CXCR5+CD8+ T cells arise in response to protein immunisation and peripheral viral infection, displaying a follicular-homing phenotype, expression of cell surface molecules associated with Tfh cells and limited cytotoxic potential. Furthermore, studies assessing the B cell response in the presence of OT-I or Cxcr5-/- OT-I cells revealed that CXCR5+CD8+ T cells shape the antibody response to protein immunisation and peripheral viral infection, promoting class switching to IgG2c in responding B cells. Overall, the results highlight a novel contribution of CD8+ T cells to antibody responses, expanding the functionality of the adaptive immune system.
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Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Virus de la Influenza A/fisiología , Gripe Humana/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptores CXCR5/metabolismo , Animales , Formación de Anticuerpos , Humanos , Inmunización , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Ovalbúmina/inmunología , Receptores CXCR5/genéticaRESUMEN
Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.
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Quimiocina CCL21/metabolismo , Inmunidad , Neoplasias/inmunología , Receptores CCR/metabolismo , Animales , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Cadenas alfa de Integrinas/metabolismo , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Neoplasias/genética , Células del Estroma/metabolismo , Análisis de SupervivenciaRESUMEN
A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.
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Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Infecciones por Coronavirus/inmunología , Citocinas/inmunología , Células Dendríticas/inmunología , Neumonía Viral/inmunología , Linfocitos T/inmunología , Anciano , Subgrupos de Linfocitos B/inmunología , Basófilos/inmunología , Betacoronavirus , COVID-19 , Estudios de Casos y Controles , Ciclo Celular , Quimiocina CXCL10/inmunología , Quimiocinas/inmunología , Estudios de Cohortes , Infecciones por Coronavirus/sangre , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Hospitalización , Humanos , Memoria Inmunológica , Inmunofenotipificación , Interleucina-10/inmunología , Interleucina-6/inmunología , Recuento de Leucocitos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Pronóstico , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Regulación hacia ArribaRESUMEN
Preprogrammed IL-17-producing γδ T cells constitute a poorly understood class of lymphocytes that express rearranged antigen receptors but appear to make little use of them. γδT17 cells were first characterized as tissue-resident sentinels with innate effector function. However, ongoing research continues to reveal unexpected complexity to this unusual subset, including phenotypic plasticity, memory-like activity and unique migratory behavior. Despite these advances, at the core of γδT17 cell biology remain fundamental gaps in knowledge: Are γδT17 cells truly innate or has the importance of the T cell receptor been overlooked? How unique are they among IL-17-producing lymphocytes? How similar are these cells between mice and humans? We speculate that answering these unresolved questions is key to successful manipulation of γδ T cells in clinical settings.
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Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Células Th17/inmunología , Animales , Humanos , Interleucina-17/inmunología , RatonesRESUMEN
The ß common ([ßc]/CD131) family of cytokines comprises granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5, all of which use ßc as their key signaling receptor subunit. This is a prototypic signaling subunit-sharing cytokine family that has unveiled many biological paradigms and structural principles applicable to the IL-2, IL-4, and IL-6 receptor families, all of which also share one or more signaling subunits. Originally identified for their functions in the hematopoietic system, the ßc cytokines are now known to be truly pleiotropic, impacting on multiple cell types, organs, and biological systems, and thereby controlling the balance between health and disease. This review will focus on the emerging biological roles for the ßc cytokines, our progress toward understanding the mechanisms of receptor assembly and signaling, and the application of this knowledge to develop exciting new therapeutic approaches against human disease.
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Citocinas/clasificación , Citocinas/metabolismo , Citocinas/genética , Regulación de la Expresión Génica/fisiología , Humanos , Inflamación/metabolismo , Sepsis/metabolismo , Transducción de SeñalRESUMEN
Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.
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Linfocitos B/citología , Linfocitos B/metabolismo , Linaje de la Célula , Receptores CCR/metabolismo , Animales , Antígenos/metabolismo , Proliferación Celular , Centro Germinal/metabolismo , Ratones Endogámicos C57BL , Bazo/citologíaRESUMEN
Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.
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Movimiento Celular , Interleucina-17/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores CCR2/metabolismo , Receptores CCR6/metabolismo , Subgrupos de Linfocitos T/citología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Quimiocinas/metabolismo , Quimiotaxis , Regulación hacia Abajo , Femenino , Homeostasis , Inflamación , Factores Reguladores del Interferón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/citologíaAsunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Esquemas de Inmunización , Inmunogenicidad Vacunal , Neoplasias/inmunología , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/inmunología , Anticuerpos Antivirales/sangre , Vacuna BNT162 , COVID-19/diagnóstico , COVID-19/inmunología , COVID-19/virología , Estudios de Casos y Controles , Citocinas/sangre , Interacciones Huésped-Patógeno , Humanos , Inmunoglobulina G/sangre , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/virología , Factores de Tiempo , Resultado del Tratamiento , VacunaciónRESUMEN
IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.