Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells
Despite advances in diagnosing latent Mycobacterium tuberculosis infection (LTBI), we still lack a diagnostic test that differentiates LTBI from active tuberculosis (TB) or predicts the risk of progression to active disease. One reason for the absence of such a test may be the failure of current ass...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02127/full |
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| author | Riccardo Arrigucci Karim Lakehal Pooja Vir Deborah Handler Amy L. Davidow Rosa Herrera Julia Dolores Estrada-Guzmán Yuri Bushkin Sanjay Tyagi Alfred A. Lardizabal Maria Laura Gennaro |
| author_facet | Riccardo Arrigucci Karim Lakehal Pooja Vir Deborah Handler Amy L. Davidow Rosa Herrera Julia Dolores Estrada-Guzmán Yuri Bushkin Sanjay Tyagi Alfred A. Lardizabal Maria Laura Gennaro |
| author_sort | Riccardo Arrigucci |
| collection | DOAJ |
| description | Despite advances in diagnosing latent Mycobacterium tuberculosis infection (LTBI), we still lack a diagnostic test that differentiates LTBI from active tuberculosis (TB) or predicts the risk of progression to active disease. One reason for the absence of such a test may be the failure of current assays to capture the dynamic complexities of the immune responses associated with various stages of TB, since these assays measure only a single parameter (release of IFN-γ) and rely on prolonged (overnight) T cell stimulation. We describe a novel, semi-automated RNA flow cytometry assay to determine whether immunological differences can be identified between LTBI and active TB. We analyzed antigen-induced expression of Th1 cytokine mRNA after short (2- and 6-h) stimulation with antigen, in the context of memory T cell immunophenotyping. IFNG and TNFA mRNA induction was detectable in CD4+ T cells after only 2 h of ex vivo stimulation. Moreover, IFNG- and TNFA-expressing CD4+ T cells (Th1 cells) were more frequent in active TB than in LTBI, a difference that is undetectable with conventional, protein-based cytokine assays. We also found that active TB was associated with higher ratios of effector memory to central memory Th1 cells than LTBI. This effector memory phenotype of active TB was associated with increased T cell differentiation, as defined by loss of the CD27 marker, but not with T cell exhaustion, as determined by PD-1 abundance. These results indicate that single-cell-based, mRNA measurements may help identify time-dependent, quantitative differences in T cell functional status between latent infection and active tuberculosis. |
| first_indexed | 2024-12-11T01:25:19Z |
| format | Article |
| id | doaj.art-2cb95bc3029543c3816a93b77671a294 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T01:25:19Z |
| publishDate | 2018-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2cb95bc3029543c3816a93b77671a2942022-12-22T01:25:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-09-01910.3389/fimmu.2018.02127412554Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 CellsRiccardo Arrigucci0Karim Lakehal1Pooja Vir2Deborah Handler3Amy L. Davidow4Rosa Herrera5Julia Dolores Estrada-Guzmán6Yuri Bushkin7Sanjay Tyagi8Alfred A. Lardizabal9Maria Laura Gennaro10Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesGlobal Tuberculosis Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesDepartment of Biostatistics, School of Public Health, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesFacultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali, MexicoFacultad de Medicina Mexicali, Universidad Autónoma de Baja California, Mexicali, MexicoPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesGlobal Tuberculosis Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesPublic Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United StatesDespite advances in diagnosing latent Mycobacterium tuberculosis infection (LTBI), we still lack a diagnostic test that differentiates LTBI from active tuberculosis (TB) or predicts the risk of progression to active disease. One reason for the absence of such a test may be the failure of current assays to capture the dynamic complexities of the immune responses associated with various stages of TB, since these assays measure only a single parameter (release of IFN-γ) and rely on prolonged (overnight) T cell stimulation. We describe a novel, semi-automated RNA flow cytometry assay to determine whether immunological differences can be identified between LTBI and active TB. We analyzed antigen-induced expression of Th1 cytokine mRNA after short (2- and 6-h) stimulation with antigen, in the context of memory T cell immunophenotyping. IFNG and TNFA mRNA induction was detectable in CD4+ T cells after only 2 h of ex vivo stimulation. Moreover, IFNG- and TNFA-expressing CD4+ T cells (Th1 cells) were more frequent in active TB than in LTBI, a difference that is undetectable with conventional, protein-based cytokine assays. We also found that active TB was associated with higher ratios of effector memory to central memory Th1 cells than LTBI. This effector memory phenotype of active TB was associated with increased T cell differentiation, as defined by loss of the CD27 marker, but not with T cell exhaustion, as determined by PD-1 abundance. These results indicate that single-cell-based, mRNA measurements may help identify time-dependent, quantitative differences in T cell functional status between latent infection and active tuberculosis.https://www.frontiersin.org/article/10.3389/fimmu.2018.02127/fullFISH-FlowT cell activationcytokineimmunophenotypingsingle-cell gene expressionmemory T cells |
| spellingShingle | Riccardo Arrigucci Karim Lakehal Pooja Vir Deborah Handler Amy L. Davidow Rosa Herrera Julia Dolores Estrada-Guzmán Yuri Bushkin Sanjay Tyagi Alfred A. Lardizabal Maria Laura Gennaro Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells Frontiers in Immunology FISH-Flow T cell activation cytokine immunophenotyping single-cell gene expression memory T cells |
| title | Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells |
| title_full | Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells |
| title_fullStr | Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells |
| title_full_unstemmed | Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells |
| title_short | Active Tuberculosis Is Characterized by Highly Differentiated Effector Memory Th1 Cells |
| title_sort | active tuberculosis is characterized by highly differentiated effector memory th1 cells |
| topic | FISH-Flow T cell activation cytokine immunophenotyping single-cell gene expression memory T cells |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02127/full |
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