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The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19. We find that IFNγ drives the development of 18fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but is not required for suppression of viral replication. In contrast, IL-10 limits the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but does not impair viral clearance. We also show that IL-10 induces the subsequent differentiation of virus-specific effector T cells into CD69+CD103+ tissue resident memory cells (Trm) in the airways and maintains Trm cells in nasal mucosal surfaces, highlighting an unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques.
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COVID-19 , Memoria Inmunológica , Interleucina-10 , Macaca mulatta , Células T de Memoria , SARS-CoV-2 , Animales , Interleucina-10/inmunología , Interleucina-10/metabolismo , COVID-19/inmunología , SARS-CoV-2/inmunología , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Memoria Inmunológica/inmunología , Pulmón/inmunología , Pulmón/virología , Pulmón/patología , Modelos Animales de Enfermedad , Interferón gamma/metabolismo , Interferón gamma/inmunología , Linfocitos T/inmunologíaRESUMEN
Background: Interleukin-17-producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined. Methods: We performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context. Results: We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17-producing CD4 T cells were preserved; we found that IL-17-producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies. Conclusions: We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.
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Antígenos Bacterianos , Infecciones por VIH , Interleucina-17 , Tuberculosis Latente , Mycobacterium tuberculosis , Células Th17 , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos Bacterianos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inmunofenotipificación , Interleucina-17/metabolismo , Interleucina-17/inmunología , Quinurenina/metabolismo , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Mycobacterium tuberculosis/inmunología , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Triptófano/metabolismoRESUMEN
How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.
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Cadenas HLA-DRB1 , Humanos , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Lactante , Población Negra/genética , Vacunas contra Hepatitis B/inmunología , Sitios de Carácter Cuantitativo , Masculino , Femenino , Uganda , Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Vacuna contra la Tos Ferina/inmunología , Vacuna contra la Tos Ferina/genética , Vacunación , Tos Ferina/prevención & control , Tos Ferina/inmunología , Tos Ferina/genéticaRESUMEN
Clinical prediction of nontuberculous mycobacteria lung disease (NTM-LD) progression remains challenging. We aimed to evaluate antigen-specific immunoprofiling utilizing flow cytometry (FC) of activation-induced markers (AIM) and IFN-γ enzyme-linked immune absorbent spot assay (ELISpot) accurately identifies patients with NTM-LD, and differentiate those with progressive from nonprogressive NTM-LD. A Prospective, single-center, and laboratory technician-blinded pilot study was conducted to evaluate the FC and ELISpot based immunoprofiling in patients with NTM-LD (n = 18) and controls (n = 22). Among 18 NTM-LD patients, 10 NTM-LD patients were classified into nonprogressive, and 8 as progressive NTM-LD based on clinical and radiological features. Peripheral blood mononuclear cells were collected from patients with NTM-LD and control subjects with negative QuantiFERON results. After stimulation with purified protein derivative (PPD), mycobacteria-specific peptide pools (MTB300, RD1-peptides), and control antigens, we performed IFN-γ ELISpot and FC AIM assays to access their diagnostic accuracies by receiver operating curve (ROC) analysis across study groups. Patients with NTM-LD had significantly higher percentage of CD4+/CD8+ T-cells co-expressing CD25+CD134+ in response to PPD stimulation, differentiating between NTM-LD and controls. Among patients with NTM-LD, there was a significant difference in CD25+CD134+ co-expression in MTB300-stimulated CD8+ T-cells (p <0.05; AUC-ROC = 0.831; Sensitivity = 75% [95% CI: 34.9-96.8]; Specificity = 90% [95% CI: 55.5-99.7]) between progressors and nonprogressors. Significant differences in the ratios of antigen-specific IFN-γ ELISpot responses were also seen for RD1-nil/PPD-nil and RD1-nil/anti-CD3-nil between patients with nonprogressive vs. progressive NTM-LD. Our results suggest that multiparameter immunoprofiling can accurately identify patients with NTM-LD and may identify patients at risk of disease progression. A larger longitudinal study is needed to further evaluate this novel immunoprofiling approach.
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Infecciones por Mycobacterium no Tuberculosas , Neumonía , Humanos , Proyectos Piloto , Estudios Prospectivos , Leucocitos Mononucleares , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no TuberculosasRESUMEN
Blockade of the co-inhibitory receptor PD-1 enhances antitumor responses by boosting the function of antigen-specific T cells. Although rare, PD-1 blockade in patients with cancer can lead to exacerbation of infection-associated pathology. Here, we detail the case of a 38-year-old man who was enrolled in a clinical trial for assessment of the safety and activity of anti-PD-1 therapy for Kaposi sarcoma in people with HIV well-controlled on antiretroviral therapy. Less than a week after receiving the first dose of anti-PD-1 antibody (pembrolizumab), he presented with severe abdominal pain associated with sudden exacerbations of preexisting cytomegalovirus (CMV) enteritis and nontuberculous mycobacterial mesenteric lymphadenitis. Plasma biomarkers of gastrointestinal tract damage were highly elevated compared with healthy controls, consistent with HIV-associated loss of gut epithelial barrier integrity. Moreover, CMV-specific CD8 T cells expressed high levels of PD-1, and 7 days following PD-1 blockade, there was an increase in the frequency of activated CD38+ Ki67+ CMV-specific CD8 T cells. This case highlights the potential for PD-1 blockade to drive rapid exacerbations of inflammatory symptoms when administered to individuals harboring multiple unresolved infections.
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Post-acute sequelae of COVID-19 (PASC), or Long COVID, is a chronic condition following acute SARS-CoV-2 infection. Symptoms include exertion fatigue, respiratory issues, myalgia, and neurological manifestations such as 'brain fog,' posing concern for their debilitating nature and potential role in other neurological disorders. However, the underlying potential pathogenic mechanisms of the neurological complications of PASC is largely unknown. Herein, we investigated differences in antigen-specific T cell responses from the peripheral blood towards SARS-CoV-2, latent viruses, or neuronal antigens in 14 PASC individuals with neurological manifestations (PASC-N) versus 22 individuals fully recovered from COVID-19. We employed Activation Induced Marker (AIM), ICS and FluoroSpot assays to determine the specificity and magnitude of CD4+ and CD8+ T cell responses towards SARS-CoV-2 (Spike and rest of proteome), latent viruses (CMV, EBV), and several neuronal antigens. Overall, we observed similar antigen-specific T cell frequencies and cytokine effector T cell responses between PASC donors compared to recovered controls for all antigens tested (viral or autoantigen) in both CD4+ and CD8+ T cell compartments. Our findings suggest that PASC-N does not appear to be associated with changes in antigen-specific T cell responses towards a subset of disease-relevant targets, but more studies in a larger cohort are needed to confirm these unaltered responses.
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Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , COVID-19 , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/complicaciones , SARS-CoV-2/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T CD8-positivos/inmunología , Femenino , Linfocitos T CD4-Positivos/inmunología , Adulto , Anciano , Autoinmunidad/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Autoantígenos/inmunologíaRESUMEN
CD4 T cells are essential for immunity to M. tuberculosis (Mtb), and emerging evidence indicates that IL-17-producing Th17 cells contribute to immunity to Mtb. While identifying protective T cell effector functions is important for TB vaccine design, T cell antigen specificity is also likely to be important. To identify antigens that induce protective immunity, we reasoned that as in other pathogens, effective immune recognition drives sequence diversity in individual Mtb antigens. We previously identified Mtb genes under evolutionary diversifying selection pressure whose products we term Rare Variable Mtb Antigens (RVMA). Here, in two distinct human cohorts with recent exposure to TB, we found that RVMA preferentially induce CD4 T cells that express RoRγt and produce IL-17, in contrast to 'classical' Mtb antigens that induce T cells that produce IFNγ. Our results suggest that RVMA can be valuable antigens in vaccines for those already infected with Mtb to amplify existing antigen-specific Th17 responses to prevent TB disease.
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Parkinson's disease (PD) is associated with autoimmune T cells that recognize the protein alpha-synuclein in a subset of individuals. Multiple neuroantigens are targets of autoinflammatory T cells in classical central nervous system autoimmune diseases such as multiple sclerosis (MS). Here, we explored whether additional autoantigenic targets of T cells in PD. We generated 15-mer peptide pools spanning several PD-related proteins implicated in PD pathology, including GBA, SOD1, PINK1, parkin, OGDH, and LRRK2. Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. This approach identified unique epitopes and their HLA restriction from the mitochondrial-associated protein PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells. The T cell reactivity was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.
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OBJECTIVES: Tuberculosis (TB) remains a global health challenge due to various factors, including delayed diagnoses leading to the spread of infection, limited efficacy of current vaccination strategies, and emergence of drug-resistant strains. Here, we explore the significance of Mycobacterium tuberculosis (Mtb)-specific antigens to overcome these challenges. METHODS: A narrative review exploring the dynamics of Mtb-specific antigens and the related T cell immune responses across the TB spectrum. RESULTS: A variety of antigens are expressed at different stages of Mtb infection, driving its diverse antigenic landscape and associated T cell functional heterogeneity. Recent advances in high-coverage genomic and proteomic approaches may lead to the identification and characterization of antigens/epitopes within the context of TB. CONCLUSION: Factors such as magnitude of memory response, cytokine profile, immunodominance, and conservation of epitopes should be emphasized as crucial parameters in assessing the potential efficacy of these antigens in diagnostics or vaccine research. Recognizing the antigenic repertoire of Mtb changes with the infection stage, it is important to assess the availability of different subsets of Mtb antigens across the spectrum of infection for more precise disease classifications. Targeting specific antigens holds promise as a pathway for developing specific immunological biomarkers to predict TB reactivation in populations.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Proteómica , Antígenos Bacterianos , Interferón gamma , Tuberculosis/diagnóstico , Tuberculosis/prevención & control , Mycobacterium tuberculosis/genética , Inmunidad , EpítoposRESUMEN
Here we describe the case of a 51 years old Italian woman with acute lymphoblastic leukemia who underwent to hematopoietic stem cell transplantation (HSCT) during SARS-COV-2 infection. She presented a prolonged COVID-19 successfully treated with dual anti SARS-COV-2 antiviral plus monoclonal antibody therapy.
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There is still incomplete knowledge of which Mycobacterium tuberculosis (Mtb) antigens can trigger distinct T cell responses at different stages of infection. Here, a proteome-wide screen of 20,610 Mtb-derived peptides in 21 patients mid-treatment for active tuberculosis (ATB) reveals IFNγ-specific T cell responses against 137 unique epitopes. Of these, 16% are recognized by two or more participants and predominantly derived from cell wall and cell processes antigens. There is differential recognition of antigens, including TB vaccine candidate antigens, between ATB participants and interferon-gamma release assay (IGRA + /-) individuals. We developed an ATB-specific peptide pool (ATB116) consisting of epitopes exclusively recognized by ATB participants. This pool can distinguish patients with pulmonary ATB from IGRA + /- individuals from various geographical locations, with a sensitivity of over 60% and a specificity exceeding 80%. This proteome-wide screen of T cell reactivity identified infection stage-specific epitopes and antigens for potential use in diagnostics and measuring Mtb-specific immune responses.
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Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis , Humanos , Epítopos de Linfocito T , Proteoma , Interferón gamma , Tuberculosis/microbiología , Tuberculosis Latente/diagnóstico , Péptidos , Antígenos BacterianosRESUMEN
Background: Interleukin 17 producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with Human Immunodeficiency Virus (HIV) disproportionately affects distinct Th17 cell subsets that respond to Mtb is incompletely defined. Methods: We performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by LC/MS on plasma and tested the hypothesis that tryptophan catabolism influences Th17 cell frequencies in this context. Results: We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+ and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3- cells of which subset 1 was significantly reduced in LTBI with HIV-ART, yet Mtb-responsive IL17-producing CD4 T cells were preserved; we found that IL17-producing CD4 T cells dominate the response to Mtb antigen but not CMV antigen or staphylococcal enterotoxin B (SEB); and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17 cell frequencies. Conclusions: We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.
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Epitopes recognized by T cells are a collection of short peptide fragments derived from specific antigens or proteins. Immunological research to study T cell responses is hindered by the extreme degree of heterogeneity of epitope targets, which are usually derived from multiple antigens; within a given antigen, hundreds of different T cell epitopes can be recognized, differing from one individual to the next because T cell epitope recognition is restricted by the epitopes' ability to bind to MHC molecules, which are extremely polymorphic in different individuals. Testing large pools encompassing hundreds of peptides is technically challenging because of logistical considerations regarding solvent-induced toxicity. To address this issue, we developed the MegaPool (MP) approach based on sequential lyophilization of large numbers of peptides that can be used in a variety of assays to measure T cell responses, including ELISPOT, intracellular cytokine staining, and activation-induced marker assays, and that has been validated in the study of infectious diseases, allergies, and autoimmunity. Here, we describe the procedures for generating and testing MPs, starting with peptide synthesis and lyophilization, as well as a step-by-step guide and recommendations for their handling and experimental usage. Overall, the MP approach is a powerful strategy for studying T cell responses and understanding the immune system's role in health and disease. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Generation of peptide pools ("MegaPools") Basic Protocol 2: MegaPool testing and quantitation of antigen-specific T cell responses.
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Linfocitos T CD8-positivos , Epítopos de Linfocito T , Humanos , Ensayo de Immunospot Ligado a Enzimas , Péptidos , Linfocitos T CD4-PositivosRESUMEN
The only licensed tuberculosis (TB) vaccine, Bacillus Calmette Guerin (BCG), fails to reliably protect adolescents and adults from pulmonary TB, resulting in ~1.6 million deaths annually. Protein subunit vaccines have shown promise against TB in clinical studies. Unfortunately, most subunit vaccines require multiple administrations, which increases the risk of loss to follow-up and necessitates more complex and costly logistics. Given the well-documented adjuvant effect of BCG, we hypothesized that BCG co-administration could compensate for a reduced number of subunit vaccinations. To explore this, we developed an expression-optimized version of our H107 vaccine candidate (H107e), which does not cross-react with BCG. In the CAF®01 adjuvant, a single dose of H107e induced inferior protection compared to three H107e/CAF®01 administrations. However, co-administering a single dose of H107e/CAF®01 with BCG significantly improved protection, which was equal to BCG co-administered with three H107e/CAF®01 doses. Importantly, combining BCG with a single H107e/CAF®01 dose also increased protection in previously BCG-primed animals. Overall, a single dose of H107e/CAF®01 with BCG induced long-lived immunity and triggered BCG-specific Th17 responses. These data support co-administration of BCG and subunit vaccines in both BCG naïve and BCG-primed individuals as an improved TB vaccine strategy with reduced number of vaccination visits.
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Antigen-specific T cells play a central role in the adaptive immune response and come in a wide range of phenotypes. T cell receptors (TCRs) mediate the antigen-specificities found in T cells. Importantly, high-throughput TCR sequencing provides a fingerprint which allows tracking of specific T cells and their clonal expansion in response to particular antigens. As a result, many studies have leveraged TCR sequencing in an attempt to elucidate the role of antigen-specific T cells in various contexts. Here, we discuss the published approaches to studying antigen-specific T cells and their specific TCR repertoire. Further, we discuss how these methods have been applied to study the TCR repertoire in various diseases in order to characterize the antigen-specific T cells involved in the immune control of disease.
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Receptores de Antígenos de Linfocitos T , Linfocitos T , Receptores de Antígenos de Linfocitos T/genética , Antígenos , Inmunidad Adaptativa , Especificidad de AnticuerposRESUMEN
Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
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Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis , Ratones , Animales , Humanos , Vacuna BCG/genética , Tuberculosis/genética , Tuberculosis/prevención & control , Mycobacterium tuberculosis/genética , Antecedentes GenéticosRESUMEN
Tuberculosis caused by Mycobacterium tuberculosis is one of the leading causes of death from a single infectious agent. Identifying dominant epitopes and comparing their reactivity in different tuberculosis (TB) infection states can help design diagnostics and vaccines. We performed a proteome-wide screen of 20,610 Mtb derived peptides in 21 Active TB (ATB) patients 3-4 months post-diagnosis of pulmonary TB (mid-treatment) using an IFNγ and IL-17 Fluorospot assay. Responses were mediated exclusively by IFNγ and identified a total of 137 unique epitopes, with each patient recognizing, on average, 8 individual epitopes and 22 epitopes (16%) recognized by 2 or more participants. Responses were predominantly directed against antigens part of the cell wall and cell processes category. Testing 517 peptides spanning TB vaccine candidates and ESAT-6 and CFP10 antigens also revealed differential recognition between ATB participants mid-treatment and healthy IGRA+ participants of several vaccine antigens. An ATB-specific peptide pool consisting of epitopes exclusively recognized by participants mid-treatment, allowed distinguishing participants with active pulmonary TB from healthy interferon-gamma release assay (IGRA)+/- participants from diverse geographical locations. Analysis of longitudinal samples indicated decreased reactivity during treatment for pulmonary TB. Together, these results show that a proteome-wide screen of T cell reactivity identifies epitopes and antigens that are differentially recognized depending on the Mtb infection stage. These have potential use in developing diagnostics and vaccine candidates and measuring correlates of protection.
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Alternative delivery routes of the current Mycobacterium tuberculosis (Mtb) vaccine, intradermally (ID) delivered BCG, may provide better protection against tuberculosis, and be more easily administered. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered via either ID or intragastric gavage vaccination. Ag-specific CD4 T cell responses in the blood were similar after BCG vaccination via gavage or ID injection. However, gavage BCG vaccination induced significantly lower T cell responses in the airways compared to intradermal BCG vaccination. Examining T cell responses in lymph node biopsies showed that ID vaccination induced T cell priming in skin-draining lymph nodes, while gavage vaccination induced priming in the gut-draining nodes, as expected. While both delivery routes induced highly functional Ag-specific CD4 T cells with a Th1* phenotype (CXCR3+CCR6+), gavage vaccination induced the co-expression of the gut-homing integrin α4ß7 on Ag-specific Th1* cells, which was associated with reduced migration into the airways. Thus, in rhesus macaques, the airway immunogenicity of gavage BCG vaccination may be limited by the imprinting of gut-homing receptors on Ag-specific T cells primed in intestinal lymph nodes. IMPORTANCE Mycobacterium tuberculosis (Mtb) is a leading cause of global infectious disease mortality. The vaccine for Mtb, Bacillus Calmette-Guérin (BCG), was originally developed as an oral vaccine, but is now given intradermally. Recently, clinical studies have reevaluated oral BCG vaccination in humans and found that it induces significant T cell responses in the airways. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered intradermally or via intragastric gavage. We find that gavage BCG vaccination induces Mtb-specific T cell responses in the airways, but to a lesser extent than intradermal vaccination. Furthermore, gavage BCG vaccination induces the gut-homing receptor a4ß7 on Mtb-specific CD4 T cells, which was associated with reduced migration into the airways. These data raise the possibility that strategies to limit the induction of gut-homing receptors on responding T cells may enhance the airway immunogenicity of oral vaccines.
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Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis , Animales , Humanos , Vacuna BCG , Macaca mulatta , Pulmón/microbiología , Tuberculosis/prevención & control , Células TH1 , Mycobacterium bovis/genética , Linfocitos T CD4-Positivos , VacunaciónRESUMEN
The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy.
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Antígenos CD5 , Linfocitos T CD8-positivos , Células Dendríticas , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Melanoma , Linfocitos T Colaboradores-Inductores , Humanos , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Células Dendríticas/inmunología , Melanoma/tratamiento farmacológico , Antígenos CD5/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2022.1009016.].