Altered peripheral blood Th17 and follicular T-helper subsets in patients with pulmonary tuberculosis

Cover Page

Cite item

Abstract

Tuberculosis (TB) is one of the most common infections worldwide. Eradication of an intracellular pathogen M. tuberculosis requires to induce a Th1 response by activating IFNγ-producing tissue macrophages. Along with Th1 cells, various subsets of Th17 and follicular T-helper cells (Tfh) able to secrete a broad range of cytokines, including IFNγ, can also be involved in eliminating bacterial pathogens. It justified analyzing in this study changes in percentage of various peripheral blood Th subsets, including Th1, Th2, Th17 and Tfh cells, in TB patients. For this, major CD3+CD4+ T cell subsets were assessed by using multicolor flow cytometry in TB patients (n = 40) and healthy volunteers (n = 30). It was found that in TB patients vs. control group percentage of peripheral blood CD45RACCR7+ central memory (CM) Th was decreased also affecting frequency of some functional T cell subsets, e.g. either lowering Th2 cells (9.11% (6.95; 13.77) vs. 7.21% (5.64; 9.84), p = 0.012) or elevating CCR6+ Th17 subsets (35.92% (27.72; 41.06) vs. 40.39% (35.41; 47.79; p = 0.016), respectively, but not influencing Th1 and Tfh subsets frequencies. Moreover, percentage of total CCR6+ CM Th cells in TB patients vs. control was decreased in CCR4CXCR3+ Th17.1 cell subset (42.87% (33.64; 49.45) vs. 52.26% (46.45; 56.95), p < 0.001), whereas standard CCR4+CXCR3 Th17 and CCR6+ DP Th17 subsets were elevated (p = 0.005 and p = 0.002, respectively). In addition, altered Tfh subset composition associated with the increased (p = 0.021) percentage of CXCR3–CCR6 Tfh2 cells, but decreased CXCR3+CCR6 Tfh1 cells (p = 0.036) was observed. Finally, frequency of peripheral blood Th subsets noted above was also analyzed within effector memory (CD45RACCR7) cells. It was found that in TB patients vs. volunteers frequency of Th17.1 cells was also significantly lower (p = 0.006) in CCR6+ EM Th (54.43% (41.19; 91.92) vs. 61.76% (54.01; 65.63), whereas percentage of double-positive Th17 was significantly increased (20.83% (15.12; 30.87) and 12.93 % (9.80; 19.01), respectively, p < 0.001). Thus, it suggests that during M. tuberculosis infection percentage of IFNγ-producing Th17 and Tfh cells was reduced compared to control group also affecting both central memory Th cells patrolling peripheral lymphoid organs as well as effector memory Th cells able to exit to site of infection. 

About the authors

I. V. Kudryavtsev

St. Petersburg State University;
Institute of Experimental Medicine;
Pavlov First St. Petersburg State Medical University

Author for correspondence.
Email: igorek1981@yandex.ru

Kudryavtsev Igor Vladimirovich., PhD (Biology), Senior Researcher, Laboratory of Immunology, Institute of Experimental Medicine; Associate Professor, Department of Immunology, Pavlov First St. Petersburg State Medical University

Russian Federation

M. K Serebriakova

Institute of Experimental Medicine

Email: m-serebryakova@yandex.ru
Serebriakova Maria Konstantinovna, Researcher, Department of Immunology Russian Federation

A. A. Starshinova

St. Petersburg State University

Email: starshinova_777@mail.ru
Starshinova Anna Andreevna, PhD, MD (Medicine), Leading Researcher, Autoimmunity Mosaic Laboratory Russian Federation

Yu. S. Zinchenko

St. Petersburg State University;
St. Petersburg Research Institute of Phthisiopulmonology

Email: ulia-zinchenko@yandex.ru
Zinchenko Yulia Sergeevna, Junior Researcher, Autoimmunity Mosaic Laboratory, St. Petersburg State University; Junior Researcher, Research Institute of Phthisiopulmonology Russian Federation

N. Yu. Basantsova

St. Petersburg State University;
St. Petersburg Research Institute of Phthisiopulmonology

Email: fromrussiawithlove_nb@mail.ru
Basantsova Natalia Yuryevna, Junior Researcher, Autoimmunity Mosaic Laboratory, Assistant Professor, Department of Faculty Therapy, St. Petersburg State University; Junior Researcher, Research Institute of Phthisiopulmonology Russian Federation

E. N. Belyaeva

"St. Petersburg Research Institute of Phthisiopulmonology" of the Ministry of Health of the Russian Federation; St. Petersburg City hospital №2

Email: starshinova_777@mail.ru
Belyaeva Ekatherine Nikolaevna, PhD (Medicine), Junior Researcher, Research Institute of Phthisiopulmonology; Head of the Department St. Petersburg City Hospital No. 2 Russian Federation

M. V. Pavlova

St. Petersburg Research Institute of Phthisiopulmonology" of the Ministry of Health of the Russian Federation

Email: starshinova_777@mail.ru
Pavlova Maria Vasil’evna, PhD, MD (Medicine), Professor, Leading Researcher, Head of Research Direction “Phthisiopulmonology” ulmonology Russian Federation

P. K. Yablonskiy

St. Petersburg State University;
St. Petersburg Research Institute of Phthisiopulmonology

Email: piotr_yablonskii@mail.ru
Yablonskii Peter Kazimirovich, PhD, MD (Medicine), Professor, Dean of the Medicine Faculty, St. Petersburg State University; Director of the Research Institute of Phthisiopulmonology Russian Federation

References

  1. Васильева Е.В., Кудрявцев И.В., Максимов Г.В., Вербов В.Н., Серебрякова М.К., Ткачук А.П., Тотолян А. А. Влияние ВИЧ-инфекции и туберкулеза на степень дифференцировки Т-лимфоцитов периферической крови //Инфекция и иммунитет. 2017. Т. 7, № 2. С. 151-161. https://doi.org/10.15789/2220-7619-2017-2-151-161
  2. Кудрявцев И.В., Борисов А.Г., Кробинец И.И., Савченко А.А., Серебрякова М.К., Тотолян А.А. Хемокиновые рецепторы на Т-хелперах различного уровня дифференцировки: основные субпопуляции. Медицинская иммунология, 2016, Т. 18, № 3, С. 239-250. doi: 10.15789/1563-0625-2016-3-239-250
  3. Кудрявцев И.В., Субботовская А.И. Опыт измерения параметров иммунного статуса с использованием шестицветного цитофлуориметрического анализа // Медицинская иммунология. 2015. Т. 17, № 1. С. 19-26. . https://doi.org/10.15789/1563-0625-2015-1-19-26
  4. Никонова А.А., Хаитов М.Р., Хаитов Р.М. Характеристика и роль различных популяций макрофагов в патогенезе острых и хронических заболеваний легких. Медицинская иммунология. 2017. Т. 19, № 6. С. 657-672. https://doi.org/10.15789/1563-0625-2017-6-657-672
  5. Соколов Д.И., Степанова О.И., Сельков С.А. Роль различных субпопуляций CD4+Т-лимфоцитов при беременности // Медицинская иммунология. 2016. Т. 18, № 6. С. 521-536. https://doi.org/10.15789/1563-0625-2016-6-521-536
  6. Хайдуков С.В., Байдун Л.А., Зурочка А.В., Тотолян Арег А. Стандартизованная технология «Исследование субпопуляционного состава лимфоцитов периферической крови с применением проточных цитофлюориметров-анализаторов» (Проект)//Медицинская иммунология. 2012. Т. 14, № 3. С. 255-268. http://dx.doi.org/10.15789/1563-0625-2012-3-255-268
  7. Arlehamn C.L., 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, vol. 193, no. 6, pp. 2931–2940. doi: 10.4049/jimmunol.1401151
  8. Chen X., Zhang M., Liao M., Graner M.W., Wu C., Yang Q., Liu H., Zhou B. Reduced Th17 response in patients with tuberculosis correlates with IL-6R expression on CD4+ T cells. Am. J. Respir. Crit. Care Med., 2010, vol. 181, no. 7, pp. 734–742. doi: 10.1164/rccm.200909-1463OC
  9. Chen Y.C., Chin C.H., Liu S.F., Wu C.C., Tsen C.C., Wang Y.H., Chao T.Y., Lie C.H., Chen C.J., Wang C.C., Lin M.C. Prognostic values of serum IP-10 and IL-17 in patients with pulmonary tuberculosis. Dis. Markers, 2011, vol. 31, no. 2, pp.101-110. doi: 10.3233/DMA-2011-0808
  10. Churchyard G., KimP., Shah N.S., Rustomjee R., Gandhi N., Mathema B., Dowdy D., Kasmar A., Cardena V. What we know about tuberculosis transmission: an overview. J. Infect. Dis., 2017, vol. 216, no. 6, pp. S629–S635. doi: 10.1093/infdis/jix362
  11. Dheda K., Chang J.S., Lala S., Huggett J.F., Zumla A., Rook G.A. Gene expression of IL17 and IL23 in the lungs of patients with active tuberculosis. Thorax, 2008, vol. 63, no. 6, pp. 566–568. doi: 10.1136/thx.2007.092205
  12. Domingo-Gonzalez R., Prince O., Cooper A., Khader S.A. Cytokines and chemokines in Mycobacterium tuberculosis Infection. Microbiol. Spectr., 2016, vol. 4, no. 5. doi: 10.1128/microbiolspec.TBTB2-0018-2016
  13. Dorhoi A., Reece S.T., Kaufmann S.H. For better or for worse: the immune response against Mycobacterium tuberculosis balances pathology and protection. Immunol. Rev., 2011, vol. 240, no. 1, pp. 235–251. doi: 10.1111/j.1600-065X.2010.00994.x
  14. Jurado J.O., Pasquinelli V., Alvarez I.B., Peña D., Rovetta A.I., Tateosian N.L., Romeo H.E., Musella R.M., Palmero D., Chuluyán H.E., García V.E. IL-17 and IFNγ expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease. J. Leukoc. Biol., 2012, vol. 91, no. 6, pp. 991–1002. doi: 10.1189/jlb.1211619
  15. Kahnert A., Höpken U.E., Stein M., Bandermann S., Lipp M., Kaufmann S.H. Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. J. Infect. Dis., 2007, vol. 195, no. 1, pp. 46–54. https://doi.org/10.1086/508894
  16. Kumar N.P., Sridhar R., Hanna L.E., Banurekha V.V., Nutman T.B., Babu S. Decreased frequencies of circulating CD4+ T follicular helper cells associated with diminished plasma IL-21 in active pulmonary tuberculosis. PLoS One, 2014, vol. 9, no. 10: e111098. doi: 10.1371/journal.pone.0111098
  17. Lyadova I.V., Panteleev A.V. Th1 and Th17 Cells in tuberculosis: protection, pathology, and biomarkers. Mediators Inflamm., 2015, vol. 2015, pp. 854507. doi: 10.1155/2015/854507
  18. Monin L., Griffiths K.L., Slight S., Lin Y., Rangel-Moreno J., Khader S.A. Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge. Mucosal Immunol., 2015, vol. 8, no. 5, pp. 1099–1109.
  19. Morita R., Schmitt N., Bentebibel S.E., Ranganathan R., Bourdery L., Zurawski G., Foucat E., Dullaers M., Oh S., Sabzghabaei N., Lavecchio E.M., Punaro M., Pascual V., Banchereau J., Ueno H. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity, 2011, vol. 34, no. 1, pp. 108–121. doi: 10.1016/j.immuni.2010.12.012
  20. Nikitina I.Y., Panteleev A.V., Kosmiadi G.A., Serdyuk Y.V., Nenasheva T.A., Nikolaev A.A., Gorelova L.A., Radaeva T.V., Kiseleva Y.Y., Bozhenko V.K., Lyadova I.V. Th1, Th17, and Th1Th17 lymphocytes during tuberculosis: Th1 lymphocytes predominate and appear as low-differentiated CXCR3+CCR6+ cells in the blood and highly differentiated CXCR3+/-CCR6cells in the lungs. J. Immunol., 2018, vol. 200, no. 6, pp. 2090–2103. doi: 10.4049/jimmunol.1701424
  21. Paulissen S.M., van Hamburg J.P., Dankers W., Lubberts E. The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis. Cytokine, 2015, vol. 74, pp. 43–53. doi: 10.1016/j.cyto.2015.02.002
  22. Phuah J.Y., Mattila J.T., Lin P.L., Flynn J.L. Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis. Am. J. Pathol., 2012, vol. 181, no. 2, pp. 508–514. doi: 10.1016/j.ajpath.2012.05.009
  23. Ramesh R., Kozhaya L., McKevitt K., Djuretic I.M., Carlson T.J., Quintero M.A., McCauley J.L., Abreu M.T., Unutmaz D., Sundrud M.S. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J. Exp. Med., 2014, vol. 211, pp. 89–104. doi: 10.1084/jem.20130301
  24. Sariko M., Maro A., Gratz J., Houpt E., Kisonga R., Mpagama S., Heysell S., Mmbaga B.T., Thomas T.A. Evaluation of cytokines in peripheral blood mononuclear cell supernatants for the diagnosis of tuberculosis. J. Inflamm. Res., 2018, vol. 12, pp. 15–22. doi: 10.1371/journal.pone.0169118
  25. Schaible U.E., Sturgill-Koszycki S., Schlesinger P.H., Russell D.G. Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages. J. Immunol., 1998, vol. 160, no. 3, pp. 1290–1296.
  26. Scriba T.J., Kalsdorf B., Abrahams D.A., Isaacs F., Hofmeister J., Black G., Hassan H.Y., Wilkinson R.J., Walzl G., Gelderbloem S.J., Mahomed H., Hussey G.D., Hanekom W.A. Distinct, specific IL-17and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response. J. Immunol., 2008, vol. 180, no. 3, pp. 1962–1970.
  27. Shu C.C., Wu M.F., Wang J.Y., Lai H.C., Lee L.N., Chiang B.L., Yu C.J. Decreased T helper 17 cells in tuberculosis is associated with increased percentages of programmed death ligand 1, T helper 2 and regulatory T cells. Respir. Res., 2017, vol. 18, no. 1, pp. 128. doi: 10.1186/s12931-017-0580-3
  28. Slight S.R., Rangel-Moreno J., Gopal R., Lin Y., Fallert Junecko B.A., Mehra S., Selman M., Becerril-Villanueva E., BaqueraHeredia J., Pavon L., Kaushal D., Reinhart T.A., Randall T.D., Khader S.A. CXCR5+ T helper cells mediate protective immunity against tuberculosis. J. Clin. Invest., 2013, vol. 123, no. 2, pp. 712–726. doi: 10.1172/JCI65728
  29. Tsai M.C., Chakravarty S., Zhu G., Xu J., Tanaka K., Koch C., Tufariello J., Flynn J., Chan J. Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension. Cell. Microbiol., 2006, vol. 8, no. 2, pp. 218–232. doi: 10.1111/j.1462-5822.2005.00612.x
  30. Ueno H., Banchereau J., Vinuesa C.G. Pathophysiology of T follicular helper cells in humans and mice. Nat. Immunol., 2015, vol. 16, no. 2, pp. 142–152. doi: 10.1038/ni.3054
  31. Wacleche V.S., Goulet J.P., Gosselin A., Monteiro P., Soudeyns H., Fromentin R., Jenabian M.A., Vartanian S., Deeks S.G., Chomont N., Routy J.P., Ancuta P. New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy. Retrovirology, 2016, vol. 13, pp. 59. doi: 10.1186/s12977-016-0293-6
  32. Wang T., Lv M., Qian Q., Nie Y., Yu L., Hou Y. Increased frequencies of T helper type 17 cells in tuberculous pleural effusion. Tuberculosis (Edinb.), 2011, vol. 91, no. 3, pp. 231–237. doi: 10.1016/j.tube.2011.02.002

Copyright (c) 2019 Kudryavtsev I.V., Serebriakova M.K., Starshinova A.A., Zinchenko Y.S., Basantsova N.Y., Belyaeva E.N., Pavlova M.V., Yablonskiy P.K.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies