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Cited by 260Sarcoidosis and Beryllium Toxicity ResearchPsoriasis: Treatment and PathogenesisT-cell and B-cell Immunology

IFN-γ–Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells

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Ramstein, Joris, Broos, Caroline E., Simpson, Laura J., Ansel, K. Mark, Sun, Sara A., Ho, Melissa E., Woodruff, Prescott G., Bhakta, Nirav R. +8 more·2016·American Journal of Respiratory and Critical Care Medicine
DOI 10.1164/rccm.201507-1499ocPMC PMC4910899
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Abstract

Rationale: Pulmonary sarcoidosis is classically defined by T-helper (Th) cell type 1 inflammation (e.g., IFN-γ production by CD4+ effector T cells). Recently, IL-17A–secreting cells have been found in lung lavage, invoking Th17 immunity in sarcoidosis. Studies also identified IL-17A–secreting cells that expressed IFN-γ, but their abundance as a percentage of total CD4+ cells was either low or undetermined. Objectives: Based on evidence that Th17 cells can be polarized to Th17.1 cells to produce only IFN-γ, our goal was to determine whether Th17.1 cells are a prominent source of IFN-γ in sarcoidosis. Methods: We developed a single-cell approach to define and isolate major Th-cell subsets using combinations of chemokine receptors and fluorescence-activated cell sorting. We subsequently confirmed the accuracy of subset enrichment by measuring cytokine production. Measurements and Main Results: Discrimination between Th17 and Th17.1 cells revealed very high percentages of Th17.1 cells in lung lavage in sarcoidosis compared with controls in two separate cohorts. No differences in Th17 or Th1 lavage cells were found compared with controls. Lung lavage Th17.1-cell percentages were also higher than Th1-cell percentages, and approximately 60% of Th17.1-enriched cells produced only IFN-γ. Conclusions: Combined use of surface markers and functional assays to study CD4+ T cells in sarcoidosis revealed a marked expansion of Th17.1 cells that only produce IFN-γ. These results suggest that Th17.1 cells could be misclassified as Th1 cells and may be the predominant producer of IFN-γ in pulmonary sarcoidosis, challenging the Th1 paradigm of pathogenesis.

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  • T cells, particularly IFNγ-producing Th17 cells, are a key immunologic feature in sarcoidosis.

    “studies indicate the involvement of T cells, particularly IFNγ -producing Th17 cells, as a key immunologic feature in sarcoidosis.”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [216]

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Research works printed but not linked: 43

  1. [1]Chen ES, Moller DR. Sarcoidosis—scientific progress and clinical challenges. Nat Rev Rheumatol. 2011;7:457–467. doi: 10.1038/nrrheum.2011.93. [DOI] [PubMed] [Google Scholar] · DOI
  2. [2]Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med. 1981;305:429–434. doi: 10.1056/NEJM198108203050804. [DOI] [PubMed] [Google Scholar] · DOI
  3. [3]Robinson BW, McLemore TL, Crystal RG. Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Invest. 1985;75:1488–1495. doi: 10.1172/JCI111852. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  4. [4]Agostini C, Meneghin A, Semenzato G. T-lymphocytes and cytokines in sarcoidosis. Curr Opin Pulm Med. 2002;8:435–440. doi: 10.1097/00063198-200209000-00016. [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Prasse A, Georges CG, Biller H, Hamm H, Matthys H, Luttmann W, Virchow JC., Jr Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells. Clin Exp Immunol. 2000;122:241–248. doi: 10.1046/j.1365-2249.2000.01365.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  6. [6]Möllers M, Aries SP, Drömann D, Mascher B, Braun J, Dalhoff K. Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis. Thorax. 2001;56:487–493. doi: 10.1136/thorax.56.6.487. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  7. [7]Wahlström J, Katchar K, Wigzell H, Olerup O, Eklund A, Grunewald J. Analysis of intracellular cytokines in CD4+ and CD8+ lung and blood T cells in sarcoidosis. Am J Respir Crit Care Med. 2001;163:115–121. doi: 10.1164/ajrccm.163.1.9906071. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Huang H, Lu Z, Jiang C, Liu J, Wang Y, Xu Z. Imbalance between Th17 and regulatory T-Cells in sarcoidosis. Int J Mol Sci. 2013;14:21463–21473. doi: 10.3390/ijms141121463. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  9. [9]Richmond BW, Ploetze K, Isom J, Chambers-Harris I, Braun NA, Taylor T, Abraham S, Mageto Y, Culver DA, Oswald-Richter KA, et al. Sarcoidosis Th17 cells are ESAT-6 antigen specific but demonstrate reduced IFN-γ expression. J Clin Immunol. 2013;33:446–455. doi: 10.1007/s10875-012-9817-6. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. [10]Ostadkarampour M, Eklund A, Moller D, Glader P, Olgart Höglund C, Lindén A, Grunewald J, Wahlström J. Higher levels of interleukin IL-17 and antigen-specific IL-17 responses in pulmonary sarcoidosis patients with Löfgren’s syndrome. Clin Exp Immunol. 2014;178:342–352. doi: 10.1111/cei.12403. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. [11]Tondell A, Moen T, Borset M, Salvesen O, Ro AD, Sue-Chu M. Bronchoalveolar lavage fluid IFN-γ+ Th17 cells and regulatory T cells in pulmonary sarcoidosis. Mediators Inflamm. 2014;2014:438070. doi: 10.1155/2014/438070. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. [12]Ten Berge B, Paats MS, Bergen IM, van den Blink B, Hoogsteden HC, Lambrecht BN, Hendriks RW, Kleinjan A. Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology (Oxford) 2012;51:37–46. doi: 10.1093/rheumatology/ker316. [DOI] [PubMed] [Google Scholar] · DOI
  13. [13]Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S, Ave E, Gattazzo C, Fadini GP, Calabrese F, et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax. 2011;66:144–150. doi: 10.1136/thx.2010.140319. [DOI] [PubMed] [Google Scholar] · DOI
  14. [14]Ramesh R, Kozhaya L, McKevitt K, Djuretic IM, Carlson TJ, Quintero MA, McCauley JL, Abreu MT, Unutmaz D, Sundrud MS. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med. 2014;211:89–104. doi: 10.1084/jem.20130301. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [15]Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, Powrie F. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010;33:279–288. doi: 10.1016/j.immuni.2010.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  16. [16]Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, et al. Fate mapping of IL-17–producing T cells in inflammatory responses. Nat Immunol. 2011;12:255–263. doi: 10.1038/ni.1993. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  17. [18]Lexberg MH, Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, Radbruch A, Chang HD. IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol. 2010;40:3017–3027. doi: 10.1002/eji.201040539. [DOI] [PubMed] [Google Scholar] · DOI
  18. [19]Sundrud MS, Trivigno C. Identity crisis of Th17 cells: many forms, many functions, many questions. Semin Immunol. 2013;25:263–272. doi: 10.1016/j.smim.2013.10.021. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  19. [20]Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Filì L, Ferri S, Frosali F, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204:1849–1861. doi: 10.1084/jem.20070663. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  20. [21]Maggi L, Santarlasci V, Capone M, Rossi MC, Querci V, Mazzoni A, Cimaz R, De Palma R, Liotta F, Maggi E, et al. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur J Immunol. 2012;42:3180–3188. doi: 10.1002/eji.201242648. [DOI] [PubMed] [Google Scholar] · DOI
  21. [22]Duhen T, Campbell DJ. IL-1β promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol. 2014;193:120–129. doi: 10.4049/jimmunol.1302734. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [23]Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA. 2010;107:14751–14756. doi: 10.1073/pnas.1003852107. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  23. [24]Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med. 1999;160:736–755. doi: 10.1164/ajrccm.160.2.ats4-99. [DOI] [PubMed] [Google Scholar] · DOI
  24. [25]Judson MA, Costabel U, Drent M, Wells A, Maier L, Koth L, Shigemitsu H, Culver DA, Gelfand J, Valeyre D, et al. The WASOG Sarcoidosis Organ Assessment Instrument: an update of a previous clinical tool. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31:19–27. [PubMed] [Google Scholar]
  25. [26]Snyder-Cappione JE, Nixon DF, Chi JC, Nguyen ML, Kirby CK, Milush JM, Koth LL. Invariant natural killer T (iNKT) cell exhaustion in sarcoidosis. Eur J Immunol. 2013;43:2194–2205. doi: 10.1002/eji.201243185. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  26. [27]Moller DR, Koth LL, Maier LA, Morris A, Drake W, Rossman M, Leader JK, Collman RG, Hamzeh N, Sweiss NJ, et al. GRADS Sarcoidosis Study Group *. Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study: sarcoidosis protocol. Ann Am Thorac Soc. 2015;12:1561–1571. doi: 10.1513/AnnalsATS.201503-172OT. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  27. [28]Meyer KC, Kaminski MJ, Calhoun WJ, Auerbach R. Studies of bronchoalveolar lavage cells and fluids in pulmonary sarcoidosis. I. Enhanced capacity of bronchoalveolar lavage cells from patients with pulmonary sarcoidosis to induce angiogenesis in vivo. Am Rev Respir Dis. 1989;140:1446–1449. doi: 10.1164/ajrccm/140.5.1446. [DOI] [PubMed] [Google Scholar] · DOI
  28. [29]Sweiss NJ, Salloum R, Gandhi S, Alegre ML, Sawaqed R, Badaracco M, Pursell K, Pitrak D, Baughman RP, Moller DR, et al. Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations. PLoS One. 2010;5:e9088. doi: 10.1371/journal.pone.0009088. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  29. [30]Braun NA, Celada LJ, Herazo-Maya JD, Abraham S, Shaginurova G, Sevin CM, Grutters J, Culver DA, Dworski R, Sheller J, et al. Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity. Am J Respir Crit Care Med. 2014;190:560–571. doi: 10.1164/rccm.201401-0188OC. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  30. [31]Moller DR. Involvement of T cells and alterations in T cell receptors in sarcoidosis. Semin Respir Infect. 1998;13:174–183. [PubMed] [Google Scholar]
  31. [32]Grunewald J, Janson CH, Eklund A, Ohrn M, Olerup O, Persson U, Wigzell H. Restricted V alpha 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J Immunol. 1992;22:129–135. doi: 10.1002/eji.1830220120. [DOI] [PubMed] [Google Scholar] · DOI
  32. [33]Sallusto F, Zielinski CE, Lanzavecchia A. Human Th17 subsets. Eur J Immunol. 2012;42:2215–2220. doi: 10.1002/eji.201242741. [DOI] [PubMed] [Google Scholar] · DOI
  33. [35]Bergeron A, Bonay M, Kambouchner M, Lecossier D, Riquet M, Soler P, Hance A, Tazi A. Cytokine patterns in tuberculous and sarcoid granulomas: correlations with histopathologic features of the granulomatous response. J Immunol. 1997;159:3034–3043. [PubMed] [Google Scholar]
  34. [36]Moller DR, Forman JD, Liu MC, Noble PW, Greenlee BM, Vyas P, Holden DA, Forrester JM, Lazarus A, Wysocka M, et al. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol. 1996;156:4952–4960. [PubMed] [Google Scholar]
  35. [37]Walker C, Bauer W, Braun RK, Menz G, Braun P, Schwarz F, Hansel TT, Villiger B. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. Am J Respir Crit Care Med. 1994;150:1038–1048. doi: 10.1164/ajrccm.150.4.7921434. [DOI] [PubMed] [Google Scholar] · DOI
  36. [38]Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, Pierce R, McClanahan TK, Sadekova S, de Waal Malefyt R. Human Th17 cells comprise heterogeneous subsets including IFN-gamma–producing cells with distinct properties from the Th1 lineage. J Immunol. 2010;185:679–687. doi: 10.4049/jimmunol.1000366. [DOI] [PubMed] [Google Scholar] · DOI
  37. [40]Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Defining the human T helper 17 cell phenotype. Trends Immunol. 2012;33:505–512. doi: 10.1016/j.it.2012.05.004. [DOI] [PubMed] [Google Scholar] · DOI
  38. [41]Shigehara K, Shijubo N, Ohmichi M, Takahashi R, Kon S, Okamura H, Kurimoto M, Hiraga Y, Tatsuno T, Abe S, et al. IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs. J Immunol. 2001;166:642–649. doi: 10.4049/jimmunol.166.1.642. [DOI] [PubMed] [Google Scholar] · DOI
  39. [42]Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994;84:4008–4027. [PubMed] [Google Scholar]
  40. [43]Facco M, Baesso I, Miorin M, Bortoli M, Cabrelle A, Boscaro E, Gurrieri C, Trentin L, Zambello R, Calabrese F, et al. Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis. J Leukoc Biol. 2007;82:946–955. doi: 10.1189/jlb.0307133. [DOI] [PubMed] [Google Scholar] · DOI
  41. [44]Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, et al. Secukinumab in Crohn’s Disease Study Group. Secukinumab, a human anti–IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61:1693–1700. doi: 10.1136/gutjnl-2011-301668. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  42. [45]Arlehamn CL, Seumois G, Gerasimova A, Huang C, Fu Z, Yue X, Sette A, Vijayanand P, Peters B. Transcriptional profile of tuberculosis antigen–specific T cells reveals novel multifunctional features. J Immunol. 2014;193:2931–2940. doi: 10.4049/jimmunol.1401151. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  43. [46]Judson MA, Baughman RP, Costabel U, Drent M, Gibson KF, Raghu G, Shigemitsu H, Barney JB, Culver DA, Hamzeh NY, et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014;44:1296–1307. doi: 10.1183/09031936.00000914. [DOI] [PubMed] [Google Scholar] · DOI

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Authors
Ramstein, J., Broos, C. E., Simpson, L. J., Ansel, K. M., Sun, S. A., Ho, M. E., Woodruff, P. G., Bhakta, N. R., Christian, L., Nguyen, C. P., Antalek, B. J., Benn, B. S., Hendriks, R. W., van den Blink, B., Kool, M., & Koth, L. L.
Affiliations
  • Division of Pulmonary and Critical Care, Department of Medicine
  • University of California, San Francisco (US)
  • Erasmus MC (NL)
  • Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, California; and
Corresponding author
Koth, Laura L.
ORCID
Venue
American Journal of Respiratory and Critical Care Medicine
Publisher
Oxford University Press (OUP)
Published
2016-06-01
Volume
193
Issue
11
Pages
1281-1291
ISSN
  • 1073-449X (ISSN-L)
  • 1535-4970
DOI
10.1164/rccm.201507-1499oc
PMC
PMC4910899
OpenAlex
W2191026300
Cited by
260
References
3
Citations by year
2026: 15 · 2025: 21 · 2024: 23 · 2023: 32 · 2022: 30 · 2021: 36 · 2020: 30 · 2019: 21 · 2018: 23 · 2017: 23 · 2016: 6
FWCI
12.77
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • American Journal of Respiratory and Critical Care Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (U01HL112696, P01HL107202, HL107202)
  • Leukemia and Lymphoma Society
Topics
  • Health Sciences › Medicine › Physiology › Sarcoidosis and Beryllium Toxicity Research
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
pulmonary sarcoidosis, Th17.1 cells, Th17 cells, Th1 cells, interferon-gamma, IL-17A, CD4+ T cells, lung lavage, T cell subsets, chemokine receptors, Th17 polarization
MeSH terms
Adult, Aged, Bronchoalveolar Lavage Fluid, Female, Flow Cytometry, Humans, Interferon-gamma, Male, Middle Aged, Sarcoidosis, Pulmonary, Th1 Cells, Th17 Cells

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