CONTENTS OF CD4+ AND CD8+ EFFECTOR MEMORY CELLS AND PROLIFERATIVE ACTIVITY OF T LYMPHOCYTES IN BRONCHIAL ASTHMA
https://doi.org/10.15789/1563-0625-2019-3-503-516
Abstract
Bronchial asthma is a chronic inflammatory disease of the respiratory tract. T-lymphocytes play a key role in pathogenesis of this allergic disease. The reduction in number of naïve T cells and the accumulation of memory T cells in bronchial asthma are accompanied by dysregulation of T lymphocyte function. In present study, we have investigated the contents of different T lymphocyte subpopulations in peripheral blood as well as in resting and PHA-stimulated cultures, along with their proliferative capacity in patients with bronchial asthma and healthy donors. The study included 10 patients with bronchial asthma (age 45.4±11.8 years). One-half of patients was in remission state, the others having been at the stage of clinical exacerbation. The group of donors was formed by healthy individuals matched by gender and age to the patients. Based on expression of cell surface markers CD45R0, CD62L and CD197 (CCR7), the CD4+ and CD8+T lymphocytes were divided into central (Tcm) and effector memory cells (Tem), naïve T lymphocytes (Tnaïve) and terminally differentiated effector cells (Temra) using flow cytometry technique. The proliferative activity of Tcm, Tem and Tnaïve was evaluated in response to PHA as a functional marker of T cells. We have found that the percentage of peripheral CD4+TemCD62L+ and CD8+TemCD62L+ cells in the patients with asthma exacerbation was significantly reduced, if compared to the donors. Following PHA stimulation, these differences in T cell subsets between the groups of patients and donors were not detectable. We performed a correlation analysis between the memory T cell contents and age of the subjects studied. It was shown that the relative amounts of CD4+ and CD8+ memory cells increased with age in asthmatics, but not in healthy donors. Analysis of mitogen-induced proliferation showed that Tcm and Tnaïve cells proliferated more actively than other subpopulations in both groups. Meanwhile, the proliferative activity of CD4+T lymphocytes and subsets of CD8+Tcm, CD4+Tcm and CD4+Tem62L was higher in the group of asthma patients in remission state than in the patients with exacerbating disease, and healthy donors. The revealed increase in the relative number of memory T cells with age suggests that these cells participate in development of bronchial asthma. Proliferative response of the studied subpopulations, which was comparable to the donor values, suggests a functional maintenance of memory T cells and naïve T lymphocytes in bronchial asthma. The increased proliferation of some T-cell subpopulations in asthmatics in remission suggests an activated state of memory T cells. The observed decrease in the number of CD4+TemCD62L+ and CD8+TemCD62L+ in patients with asthma exacerbation may be, by our opinion, associated with an active inflammatory process in the airways.
About the Authors
M. Sh. BarkovskayaRussian Federation
MD, Junior Research Associate, Laboratory of Clinical Immunopathology
630099, Novosibirsk, Yadrintsevskaya str., 14.
Phone: 7 (383) 227-01-35. Phone/Fax: 7 (383) 222-70-28.
E. A. Blinova
Russian Federation
PhD (Biology), Senior Research Associate, Laboratory of Clinical Immunopathology
Novosibirsk
L. V. Grishina
Russian Federation
PhD (Biology), Research Associate, Laboratory of Clinical Immunopathology
Novosibirsk
M. I. Leonova
Russian Federation
MD, Allergologist-Immunologist, Department of Allergology
Novosibirsk
V. M. Nepomniashchikch
Russian Federation
MD, Allergologist-Immunologist, Department of Allergology
Novosibirsk
D. V. Demina
Russian Federation
MD, PhD (Medicine), Allergologist-Immunologist, Head, Department of Allergology
Novosibirsk
V. A. Kozlov
Russian Federation
MD, DC (Medicine), Professor, Full Member, Russian Academy of Sciences, Head, Laboratory of Clinical Immunopathology, Scientific Director
Novosibirsk
References
1. Toptygina A.P., Semikina E.L., Kopyltsova E.A., Alyoshkin V.A. Age-dependent dynamics of the CD45 isoforms expression on the T helper and T cytotoxic lymphocytes in the blood of the healthy people. Immunologiya = Immunology, 2014, Vol. 35, no. 4, pp. 229-232. (In Russ.)
2. Abdulamir A.S., Hafidh R.R., Abubakar F., Abbas K.A. Changing survival, memory cell compartment, and T-helper balance of lymphocytes between severe and mild asthma. BMC Immunol., 2008, Vol. 9, p. 73.
3. Amelink M., de Groot J.C., de Nijs S.B., Lutter R., Zwinderman A.H., Sterk P.J., ten Brinke A., Bel E.H. Severe adult-onset asthma: A distinct phenotype. J. Allergy Clin. Immunol., 2013, Vol. 132, no. 2, pp. 336-341.
4. Chen Z., Pan J., Jia Y., Li D., Min Z., Su X., Yuan H., Shen G., Cao S., Zhu L., Wang X. Effect of memory CD4+ T-cells’ signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma. Cell Biol. Toxicol., 2017, Vol. 33, no. 1, pp. 27-39.
5. den Otter I., Willems L.N.A., van Schadewijk A., van Wijngaarden S., Janssen K., de Jeu R.C., Sont J.K., Sterk P.J., Hiemstra P.S. Lung function decline in asthma patients with elevated bronchial CD8, CD4 and CD3 cells. Eur. Respir. J., 2016, Vol. 48, no. 2, pp. 393-402.
6. Endo H., Iwamoto I., Nakajima H., Yoshida S. In vitrointerleukin-5 production of peripheral blood mononuclear cells is increased in patients with asthma. Int. Arch. Allergy Immunol., 1993, Vol. 101, no. 4, pp. 425- 430.
7. Fox A., Harland K.L., Kedzierska K., Kelso A. Exposure of human CD8 + T cells to type-2 cytokines impairs division and differentiation and induces limited polarization. Front. Immunol., 2018, Vol. 9, 1141. doi: 10.3389/fimmu.2018.01141.
8. Geginat J., Lanzavecchia A., Sallusto F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood, 2003, Vol. 101, no. 11, pp. 4260-4266.
9. Geginat J., Sallusto F., Lanzavecchia A. Cytokine-driven proliferation and differentiation of human naïve, central memory, and effector memory CD4 + T cells. Pathol. Biol., 2003, Vol. 51, no. 2, pp. 64-66.
10. Global Initiative for asthma. Global Strategy for asthma management and prevention (2018 updated). Electronic resource. Access mode: https://ginasthma.org/2018-pocket-guide-for-asthma-management-andprevention/.
11. Hondowicz B.D., An D.,. Schenkel J.M., Kim K.S., Steach H.R., Krishnamurty A.T., Keitany G.J., Garza E.N., Fraser K.A., Moon J.J., Altemeier W.A., Masopust D., Pepper M. Interleukin-2-dependent allergen-specific tissue resident memory cells drive asthma. Immunity, 2016, Vol. 44, no. 1, pp. 155-166.
12. Jiang T., Sheng J., Qin Y., Xiong H., Gong Y., Tang H., Zhou J., Deng Z., Zhang H., Cui Y., Qian J., Shen Y., Jin Y. Enhanced proliferationand defective activation-induced cell deathof CD4 + T cellsin childhood asthma. Asian Pac. J. Allergy Immunol., 2014, Vol. 32, no. 1, pp. 75-83.
13. Lamb J.P., James A., Carroll N., Siena L., Elliot J., Vignola A.M. Reduced apoptosis of memory T-cells in the inner airway wall of mild and severe asthma. Eur. Respir. J., 2005, Vol. 26, no. 2, pp. 265-270.
14. Lloyd C.M., Hessel E.M. Functions of T cells in asthma: more than just Th2 cells. Nat. Rev. Immunol., 2010, Vol. 10, no. 12, pp. 838-848.
15. Mahnke Y.D., Brodie T.M., Sallusto F., Roederer M., Lugli E. The who’s who of T-cell differentiation: human memory T-cell subsets. Eur. J. Immunol., 2013, Vol. 43, no. 11, pp. 2797-2809.
16. Maldonado A., Mueller Y.M., Thomas P., Bojczuk P., O’Connors C., Katsikis P.D. Decreased effector memory CD45RA+ CD62L– CD8+T cells and increased central memory CD45RA – CD62L+ CD8+ T cells in peripheral blood of rheumatoid arthritis patients. Arthritis Res. Therapy, 2003, Vol. 5, no. 2, pp. R91-R96.
17. Matsuzaki S., Shinozaki K., Kobayashi N., Agematsu K. Polarization of Th1/Th2 in human CD4+ T cells separated by CD62L: analysis by transcription factors. Allergy, 2005, Vol. 60, no. 6, pp. 780-787.
18. Miranda C., Busacker A., Balzar S., Trudeau J., Wenzel S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J. Allergy Clin. Immunol., 2004, Vol. 113, no. 1, pp. 101-108.
19. O’Sullivan S., Cormican L., Faul J.L., Ichinohe S., Johnston S.L., Burke C.M., Poulter L.W. Activated, cytotoxic CD8 + T lymphocytes contribute to the pathology of asthma death. Am. J. Respir. Crit. Care Med., 2001, Vol. 164, no. 4, pp. 560-564.
20. Robinson D.S., Bentley A.M., Hartnell A., Kay A.B., Durham S.R. Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax, 1993, Vol. 48, no. 1, pp. 26-32.
21. Sallusto F., Lenig D., Förster R., Lipp M., Lanzavecchia A. Two subsetsof memory T lymphocyteswith distinct homing potentialsand effector functions. Nature, 1999, Vol. 401, no. 6754, pp. 708-712.
22. Sprent J., Surh C.D. Normal T cell homeostasis: the conversion of naïve cells into memory-phenotype cells. Nat. Immunol., 2011, Vol. 12, no. 6, pp. 478-484.
23. Tang C., Rolland J.M., Ward C., Bish R., Thien F., Walters E.H. Seasonal comparison of cytokine profiles in atopic asthmatics and atopic non-asthmatics. Am. J. Respir. Crit. Care Med., 1996, Vol. 154, no. 6, pp. 1615-1622.
24. Todo-Bom A., Mota-Pinto A., Alves V., Santos-Rosa M. Aging and asthma – сhanges in CD45RA, CD29 and CD95 T cells subsets. Allergol. Imunopatol., 2012, Vol. 40, no. 1, pp. 14-19.
25. Turner D.L., Goldklang M., Cvetkovski F., Paik D., Trischler J., Barahona J., Cao M., Dave R., Tanna N., D’Armiento J.M., Farber D.L. Biased generation and in situ activation of lung tissue-resident memory CD4 T cells in the pathogenesis of allergic asthma. J. Immunol., 2018, Vol. 200, no. 5, pp. 1561-1569.
26. van Rensen E.L.J., Sont J.K., Evertse C.E., Willems L.N.A., Mauad T., Hiemstra P.S., Sterk P.J. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am. J. Respir. Crit. Care Med., 2005, Vol. 172, no. 7, pp. 837-841.
27. Weng N., Levine B.L., June C.H., Hodes R.J., Human naïve and memory T lymphocytes differ in telomeric length and replicative potential. Proc. Natl. Acad. Sci. USA, 1995, Vol. 92, no. 24, pp. 11091-11094.
28. Wiest M., Upchurch K., Yin W., Ellis J., Xue Y., Lanier B., Millard M., Joo H.M., Oh S.K. Clinical implications of CD4 + T cell subsets in adult atopic asthma patients. Allergy Asthma Clin. Immunol., 2018, Vol. 14, Article no. 7. doi:10.1186/s13223-018-0231-3.
29. Wisniewski J.A., Muehling L.M., Eccles J.D., Capaldo B.J., Agrawal R., Shirley D.A., Patrie J.T., Workman L.J., Schuyler A.J., Lawrence M.G., Teague W.G., Woodfolk J.A. TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J. Allergy Clin. Immunol., 2018, Vol. 141, no. 6, pp. 2048-2060.
Review
For citations:
Barkovskaya M.Sh., Blinova E.A., Grishina L.V., Leonova M.I., Nepomniashchikch V.M., Demina D.V., Kozlov V.A. CONTENTS OF CD4+ AND CD8+ EFFECTOR MEMORY CELLS AND PROLIFERATIVE ACTIVITY OF T LYMPHOCYTES IN BRONCHIAL ASTHMA. Medical Immunology (Russia). 2019;21(3):503-516. (In Russ.) https://doi.org/10.15789/1563-0625-2019-3-503-516