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The role of CD8+ Granzyme B+ T cells in the pathogenesis of Takayasu’s arteritis

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Abstract

Objective

T cell-mediated immune response plays a key role in Takayasu arteritis (TAK). Although previous studies have showed the roles of CD4+T cell and its subsets in TAK, the change of CD8+ T cell subsets remains unclear. This study investigated the role of CD8+ T cell subsets in TAK.

Methods

The study consisted of 56 TA patients and 51 healthy controls. The percentages of CD8+T cells, CD8+GranzymeB+ T cells, CD8+Perforin+ T cells, and CD8+IFN-γ+ T cells in blood samples were analyzed by flow cytometry.

Results

We found that the percentages of CD8+GranzymeB+ T cells (P = 0.030), CD8+Perforin+ T cells (P = 0.000), and CD8+IFN-γ+ T cells (P = 0.002) in CD8+T cells were higher in TAK patients compared to control group. After 6 months of treatment, the proportion of CD8+T cells in lymphocytes were significantly lower in TAK patients than the baseline assessment (P = 0.033). A lower ratio of CD8+GranzymeB+ T cells/CD8+ T cells were showed in TAK patents after treatment compared with TAK patients before treatments (P = 0.011). The change of CD8+GranzymeB+ T cells/CD8+ T cells ratio was positively correlated with the change of ITAS (r = 0.721, P = 0.002) and ITAS-A (r = 0.637, P = 0.008). Finally, the immunofluorescence staining showed the infiltration of CD8+ Granzyme B + cells in the aortic tissue of TAK patients.

Conclusion

Our results disclose that the CD8+ T lymphocytes may play a role in TAK pathogenesis. Targeting CD8+GranzymeB+ T lymphocytes or Granzyme B inhibitors could be a potential therapeutic approach for the treatment of TAK.

Key Points

• Our study investigated role the of CD8+ T cell subsets in TAK.

• We found the percentages of CD8+GranzymeB+ T cells, CD8+Perforin+ T cells, and CD8+IFN-γ+ T cells in CD3+CD8+T cells were higher in TAK patients.

• The proportion of CD8+T cells in lymphocytes and the ratio of CD8+GranzymeB+ T cells/CD8+ T cells were significantly lower in TAK patients after treatment.

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References

  1. Zaldivar Villon MLF, de la Rocha JAL, Espinoza LR (2019) Takayasu arteritis: recent developments. Curr Rheumatol Rep 21(9):45. https://doi.org/10.1007/s11926-019-0848-3

    Article  PubMed  CAS  Google Scholar 

  2. Tombetti E, Mason JC (2019) Takayasu arteritis: advanced understanding is leading to new horizons. Rheumatology (Oxford) 58(2):206–219. https://doi.org/10.1093/rheumatology/key040

    Article  CAS  Google Scholar 

  3. Weyand CM, Goronzy JJ (2003) Medium- and large-vessel vasculitis. N Engl J Med 349(2):160–169. https://doi.org/10.1056/NEJMra022694

    Article  PubMed  CAS  Google Scholar 

  4. Kermani TA (2019) Takayasu arteritis and giant cell arteritis: are they a spectrum of the same disease? Int J Rheum Dis 22(Suppl 1):41–48. https://doi.org/10.1111/1756-185X.13288

    Article  PubMed  Google Scholar 

  5. de Souza AW, de Carvalho JF (2014) Diagnostic and classification criteria of Takayasu arteritis. J Autoimmun 48–49:79–83. https://doi.org/10.1016/j.jaut.2014.01.012

    Article  PubMed  CAS  Google Scholar 

  6. Watanabe Y, Miyata T, Tanemoto K (2015) Current clinical features of new patients with Takayasu arteritis observed from cross-country research in Japan: age and sex specificity. Circulation 132(18):1701–1709. https://doi.org/10.1161/CIRCULATIONAHA.114.012547

    Article  PubMed  Google Scholar 

  7. Espinoza JL, Ai S, Matsumura I (2018) New insights on the pathogenesis of Takayasu arteritis: revisiting the microbial theory. Pathogens 7 (3). https://doi.org/10.3390/pathogens7030073

  8. Li T, Gao N, Cui W, Zhao L, Pan L (2020) Natural killer cells and their function in Takayasu’s arteritis. Clin Exp Rheumatol 38(Suppl 124 (2)):84–90

    PubMed  Google Scholar 

  9. Keser G, Aksu K, Direskeneli H (2018) Discrepancies between vascular and systemic inflammation in large vessel vasculitis: an important problem revisited. Rheumatology (Oxford) 57(5):784–790. https://doi.org/10.1093/rheumatology/kex333

    Article  CAS  Google Scholar 

  10. Weyand CM, Goronzy JJ (2013) Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol 9(12):731–740. https://doi.org/10.1038/nrrheum.2013.161

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Palmer E (2003) Negative selection–clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol 3(5):383–391. https://doi.org/10.1038/nri1085

    Article  PubMed  CAS  Google Scholar 

  12. Caza T, Landas S (2015) Functional and phenotypic plasticity of CD4(+) T cell subsets. Biomed Res Int 2015:521957. https://doi.org/10.1155/2015/521957

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Samson M, Corbera-Bellalta M, Audia S, Planas-Rigol E, Martin L, Cid MC, Bonnotte B (2017) Recent advances in our understanding of giant cell arteritis pathogenesis. Autoimmun Rev 16(8):833–844. https://doi.org/10.1016/j.autrev.2017.05.014

    Article  PubMed  CAS  Google Scholar 

  14. Saadoun D, Garrido M, Comarmond C, Desbois AC, Domont F, Savey L, Terrier B, Geri G, Rosenzwajg M, Klatzmann D, Fourret P, Cluzel P, Chiche L, Gaudric J, Koskas F, Cacoub P (2015) Th1 and Th17 cytokines drive inflammation in Takayasu arteritis. Arthritis Rheumatol 67(5):1353–1360. https://doi.org/10.1002/art.39037

    Article  PubMed  CAS  Google Scholar 

  15. Gao N, Cui W, Zhao LM, Li TT, Zhang JH, Pan LL (2020) Contribution of Th2-like Treg cells to the pathogenesis of Takayasu’s arteritis. Clin Exp Rheumatol 38 Suppl 124(2):48–54

  16. Pan LL, Du J, Gao N, Liao H, Wan J, Ci WP, Yang C, Wang T (2016) IL-9-producing Th9 cells may participate in pathogenesis of Takayasu’s arteritis. Clin Rheumatol 35(12):3031–3036. https://doi.org/10.1007/s10067-016-3399-2

    Article  PubMed  Google Scholar 

  17. Uppal SS, Verma S (2003) Analysis of the clinical profile, autoimmune phenomena and T cell subsets (CD4 and CD8) in Takayasu’s arteritis: a hospital-based study. Clin Exp Rheumatol 21(6 Suppl 32):S112-116

    PubMed  CAS  Google Scholar 

  18. Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, Hoffman GS (1994) Takayasu arteritis. Ann Intern Med 120(11):919–929. https://doi.org/10.7326/0003-4819-120-11-199406010-00004

    Article  PubMed  CAS  Google Scholar 

  19. Misra R, Danda D, Rajappa SM, Ghosh A, Gupta R, Mahendranath KM, Jeyaseelan L, Lawrence A, Bacon PA, Vasculitis IR, g, (2013) Development and initial validation of the Indian Takayasu clinical activity score (ITAS2010). Rheumatology (Oxford) 52(10):1795–1801. https://doi.org/10.1093/rheumatology/ket128

    Article  PubMed  Google Scholar 

  20. Lee H, Sun Y, Patti-Diaz L, Hedrick M, Ehrhardt AG (2019) High-throughput analysis of clinical flow cytometry data by automated gating. Bioinform Biol Insights 13:1177932219838851. https://doi.org/10.1177/1177932219838851

    Article  PubMed  PubMed Central  Google Scholar 

  21. Grayson PC, Maksimowicz-McKinnon K, Clark TM, Tomasson G, Cuthbertson D, Carette S, Khalidi NA, Langford CA, Monach PA, Seo P, Warrington KJ, Ytterberg SR, Hoffman GS, Merkel PA (2012) Distribution of arterial lesions in Takayasu’s arteritis and giant cell arteritis. Ann Rheum Dis 71(8):1329–1334. https://doi.org/10.1136/annrheumdis-2011-200795

    Article  PubMed  Google Scholar 

  22. Arnaud L, Haroche J, Mathian A, Gorochov G, Amoura Z (2011) Pathogenesis of Takayasu’s arteritis: a 2011 update. Autoimmun Rev 11(1):61–67. https://doi.org/10.1016/j.autrev.2011.08.001

    Article  PubMed  CAS  Google Scholar 

  23. Dos Santos JP, Artigiani Neto R, Mangueira CLP, Filippi RZ, Gutierrez PS, Westra J, Brouwer E, de Souza AWS (2020) Associations between clinical features and therapy with macrophage subpopulations and T cells in inflammatory lesions in the aorta from patients with Takayasu arteritis. Clin Exp Immunol 202(3):384–393. https://doi.org/10.1111/cei.13489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Nityanand S, Giscombe R, Srivastava S, Hjelmstrom P, Sanjeevi CB, Sinha N, Grunewald J, Lefvert AK (1997) A bias in the alphabeta T cell receptor variable region gene usage in Takayasu’s arteritis. Clin Exp Immunol 107(2):261–268. https://doi.org/10.1111/j.1365-2249.1997.295-ce1186.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Matsumoto K, Suzuki K, Yoshimoto K, Seki N, Tsujimoto H, Chiba K, Takeuchi T (2019) Significant association between clinical characteristics and changes in peripheral immuno-phenotype in large vessel vasculitis. Arthritis Res Ther 21(1):304. https://doi.org/10.1186/s13075-019-2068-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Gravano DM, Hoyer KK (2013) Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 45:68–79. https://doi.org/10.1016/j.jaut.2013.06.004

    Article  PubMed  CAS  Google Scholar 

  27. Samson M, Ly KH, Tournier B, Janikashvili N, Trad M, Ciudad M, Gautheron A, Devilliers H, Quipourt V, Maurier F, Meaux-Ruault N, Magy-Bertrand N, Manckoundia P, Ornetti P, Maillefert JF, Besancenot JF, Ferrand C, Mesturoux L, Labrousse F, Fauchais AL, Saas P, Martin L, Audia S, Bonnotte B (2016) Involvement and prognosis value of CD8(+) T cells in giant cell arteritis. J Autoimmun 72:73–83. https://doi.org/10.1016/j.jaut.2016.05.008

    Article  PubMed  CAS  Google Scholar 

  28. Boita M, Guida G, Circosta P, Elia AR, Stella S, Heffler E, Badiu I, Martorana D, Mariani S, Rolla G, Cignetti A (2014) The molecular and functional characterization of clonally expanded CD8+ TCR BV T cells in eosinophilic granulomatosis with polyangiitis (EGPA). Clin Immunol 152(1–2):152–163. https://doi.org/10.1016/j.clim.2014.03.001

    Article  PubMed  CAS  Google Scholar 

  29. Kurata A, Saito A, Hashimoto H, Fujita K, Ohno SI, Kamma H, Nagao T, Kobayashi S, Yamashina A, Kuroda M (2019) Difference in immunohistochemical characteristics between Takayasu arteritis and giant cell arteritis: it may be better to distinguish them in the same age. Mod Rheumatol:1–10. https://doi.org/10.1080/14397595.2019.1570999

  30. de Araujo-Souza PS, Hanschke SC, Viola JP (2015) Epigenetic control of interferon-gamma expression in CD8 T cells. J Immunol Res 2015:849573. https://doi.org/10.1155/2015/849573

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bertoletti A, Ferrari C (2016) Adaptive immunity in HBV infection. J Hepatol 64(1 Suppl):S71–S83. https://doi.org/10.1016/j.jhep.2016.01.026

    Article  PubMed  CAS  Google Scholar 

  32. Deng Q, Luo Y, Chang C, Wu H, Ding Y, Xiao R (2019) The emerging epigenetic role of cd8+t cells in autoimmune diseases: a systematic review. Front Immunol 10:856. https://doi.org/10.3389/fimmu.2019.00856

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Prakash MD, Munoz MA, Jain R, Tong PL, Koskinen A, Regner M, Kleifeld O, Ho B, Olson M, Turner SJ, Mrass P, Weninger W, Bird PI (2014) Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling. Immunity 41(6):960–972. https://doi.org/10.1016/j.immuni.2014.11.012

    Article  PubMed  CAS  Google Scholar 

  34. Bovenschen N, Kummer JA (2010) Orphan granzymes find a home. Immunol Rev 235(1):117–127. https://doi.org/10.1111/j.0105-2896.2010.00889.x

    Article  PubMed  CAS  Google Scholar 

  35. Boivin WA, Cooper DM, Hiebert PR, Granville DJ (2009) Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab Invest 89(11):1195–1220. https://doi.org/10.1038/labinvest.2009.91

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Mollah ZU, Graham KL, Krishnamurthy B, Trivedi P, Brodnicki TC, Trapani JA, Kay TW, Thomas HE (2012) Granzyme B is dispensable in the development of diabetes in non-obese diabetic mice. PLoS ONE 7(7):e40357. https://doi.org/10.1371/journal.pone.0040357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Blanco P, Pitard V, Viallard JF, Taupin JL, Pellegrin JL, Moreau JF (2005) Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 52(1):201–211. https://doi.org/10.1002/art.20745

    Article  PubMed  CAS  Google Scholar 

  38. Parkinson LG, Toro A, Zhao H, Brown K, Tebbutt SJ, Granville DJ (2015) Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation. Aging Cell 14(1):67–77. https://doi.org/10.1111/acel.12298

    Article  PubMed  CAS  Google Scholar 

  39. Saito Y, Kondo H, Hojo Y (2011) Granzyme B as a novel factor involved in cardiovascular diseases. J Cardiol 57(2):141–147. https://doi.org/10.1016/j.jjcc.2010.10.001

    Article  PubMed  Google Scholar 

  40. Annunziato F, Romagnani C, Romagnani S (2015) The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol 135(3):626–635. https://doi.org/10.1016/j.jaci.2014.11.001

    Article  CAS  Google Scholar 

  41. Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101. https://doi.org/10.1016/S0065-2776(07)96002-2

    Article  PubMed  CAS  Google Scholar 

  42. Tripathy NK, Chauhan SK, Nityanand S (2004) Cytokine mRNA repertoire of peripheral blood mononuclear cells in Takayasu’s arteritis. Clin Exp Immunol 138(2):369–374. https://doi.org/10.1111/j.1365-2249.2004.02613.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Savioli B, Abdulahad WH, Brouwer E, Kallenberg CGM, de Souza AWS (2017) Are cytokines and chemokines suitable biomarkers for Takayasu arteritis? Autoimmun Rev 16(10):1071–1078. https://doi.org/10.1016/j.autrev.2017.07.023

    Article  PubMed  CAS  Google Scholar 

  44. Bhat P, Leggatt G, Waterhouse N, Frazer IH (2017) Interferon-gamma derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis 8(6):e2836. https://doi.org/10.1038/cddis.2017.67

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Regnier P, Le Joncour A, Maciejewski-Duval A, Desbois AC, Comarmond C, Rosenzwajg M, Klatzmann D, Cacoub P, Saadoun D (2020) Targeting JAK/STAT pathway in Takayasu’s arteritis. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2019-216900

    Article  PubMed  Google Scholar 

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Funding

The present study was supported by grants from National Natural Science Foundation of China (91739111, 81900448).

Author information

Authors and Affiliations

  1. Department of Rheumatology, Capital Medical University Affiliated Anzhen Hospital, Beijing, China

    Taotao Li, Na Gao, Juan Du, Xuemei Shi & Lili Pan

  2. Beijing Institute of Heart, Lung and Vessel Disease, Capital Medical University Affiliated Anzhen Hospital, Beijing, China

    Wei Cui & Limin Zhao

  3. Department of Cardiovascular Surgery, Capital Medical University Affiliated Anzhen Hospital, Beijing, China

    Junming Zhu, Zhiyu Qiao & Shichao Guo

Authors
  1. Taotao Li
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  2. Na Gao
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  3. Wei Cui
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  4. Limin Zhao
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  5. Juan Du
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  6. Xuemei Shi
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  7. Junming Zhu
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  8. Zhiyu Qiao
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  9. Shichao Guo
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  10. Lili Pan
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Contributions

Lili Pan contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Taotao Li, Na Gao, Juan Du, and Xuemei Shi. Junming Zhu, Zhiyu Qiao and Shichao Guo collected the samples. Wei Cui and Limin Zhao performed the experiments. The first draft of the manuscript was written by Taotao Li. Lili Pan is the corresponding author of the manuscript who guided the writing and made the corrections of the whole paper. All authors declare no potential conflicts of interest.

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Correspondence to Lili Pan.

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This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Anzhen Hospital (approval no. 2019067X).

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Li, T., Gao, N., Cui, W. et al. The role of CD8+ Granzyme B+ T cells in the pathogenesis of Takayasu’s arteritis. Clin Rheumatol 41, 167–176 (2022). https://doi.org/10.1007/s10067-021-05903-4

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