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Effect of different cytokines in combination with IL-15 on the expression of activating receptors in NK cells of patients with Behçet’s disease

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Abstract

Behçet’s disease (BD) is a systemic, autoinflammatory, chronic disorder which affects various parts of the body in genetically susceptible individuals. BD has a multi-factorial etiopathogenesis which encompasses both innate and adaptive arms of immunity. NK cells, which kill virus-infected or malign cells and provide interaction between adaptive and innate immune system, are also known to involve in the pathogenesis of autoimmune/autoinflammatory diseases including BD. NK cells function in immune responses via the signals obtained from surface-expressed activating and inhibitory receptors. In this study, we aimed to explore NK cell activation status by measuring the levels of activation marker CD69 and activating receptors NKG2D, NKp30, and NKp46 as well as proliferative and cytotoxic capacities in response to stimulation with interleukin (IL)-15-combined cytokines in BD patients. CD4+ and CD8+ T cell responses were also evaluated to compare with those of NK cells. As a result, the expression of activating receptors on NK cells was demonstrated to be varied among patients with active and inactive BD and healthy controls. The proliferation levels of NK cells were elevated in BD patients, especially in inactive phase of disease compared to healthy controls. Additionally, CD107a levels of inactive BD patients were detected to be lower in comparison with healthy controls and active BD patients. These findings suggest that BD patients in active and inactive phases display different activation status of NK cells which indicate NK cells might be associated with immune attacks and remissions during the course of BD.

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References

  1. Behcet H, Matteson EL. On relapsing, aphthous ulcers of the mouth, eye and genitalia caused by a virus. 1937. Clin Exp Rheumatol. 2010;28(4 Suppl 60):S2-5.

    PubMed  Google Scholar 

  2. Nieto IG, Alabau JLC. Immunopathogenesis of Behcet Disease. Curr Rheumatol Rev. 2020;16(1):12–20.

    Article  CAS  PubMed  Google Scholar 

  3. Adil A, et al. Behcet disease. Treasure Island (FL): StatPearls Publishing; 2022.

  4. Hatemi G, et al. One year in review 2020: Behcet’s syndrome. Clin Exp Rheumatol. 2020;38 Suppl 127(5):3–10.

    Article  PubMed  Google Scholar 

  5. Tong B, et al. Immunopathogenesis of Behcet’s disease. Front Immunol. 2019;10:665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Parlakgul G, et al. Expression of regulatory receptors on gammadelta T cells and their cytokine production in Behcet’s disease. Arthritis Res Ther. 2013;15(1):R15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deuter CM, et al. Behcet’s disease: ocular effects and treatment. Prog Retin Eye Res. 2008;27(1):111–36.

    Article  CAS  PubMed  Google Scholar 

  8. Salmaninejad A, et al. Genetics and immunodysfunction underlying Behcet’s disease and immunomodulant treatment approaches. J Immunotoxicol. 2017;14(1):137–51.

    Article  CAS  PubMed  Google Scholar 

  9. Clemente Ximenis A, et al. In vitro evaluation of gammadelta T cells regulatory function in Behcet’s disease patients and healthy controls. Hum Immunol. 2016;77(1):20–8.

    Article  CAS  PubMed  Google Scholar 

  10. Zhou ZY, et al. Cytokines and Behcet’s disease. Autoimmun Rev. 2012;11(10):699–704.

    Article  CAS  PubMed  Google Scholar 

  11. Kaneko F, et al. Natural killer cell numbers and function in peripheral lymphoid cells in Behcet’s disease. Br J Dermatol. 1985;113(3):313–8.

    Article  CAS  PubMed  Google Scholar 

  12. Kucuksezer UC, et al. The role of natural killer cells in autoimmune diseases. Front Immunol. 2021;12:622306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Horton NC, Mathew PA. NKp44 and natural cytotoxicity receptors as damage-associated molecular pattern recognition receptors. Front Immunol. 2015;6:31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Pegram HJ, et al. Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol. 2011;89(2):216–24.

    Article  PubMed  Google Scholar 

  15. Zingoni A, et al. NKG2D and its ligands: “One for All, All for One.” Front Immunol. 2018;9:476.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hudspeth K, Silva-Santos B, Mavilio D. Natural cytotoxicity receptors: broader expression patterns and functions in innate and adaptive immune cells. Front Immunol. 2013;4:69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Zwirner NW, Ziblat A. Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: the case of IL-27. Front Immunol. 2017;8:25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Zhang J. Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease. J Clin Invest. 2007;117(4):871–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yasuda K, et al. Interleukin-18 in health and disease. Int J Mol Sci. 2019;20(3).

  20. Fehniger TA, et al. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol. 1999;162(8):4511–20.

    CAS  PubMed  Google Scholar 

  21. Romee R, Leong JW, Fehniger TA. Utilizing cytokines to function-enable human NK cells for the immunotherapy of cancer. Scientifica (Cairo). 2014;2014:205796.

    PubMed Central  Google Scholar 

  22. Nielsen CM, et al. Synergy between common gamma chain family cytokines and IL-18 potentiates innate and adaptive pathways of NK cell activation. Front Immunol. 2016;7:101.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Carson W, Caligiuri MA. Interleukin-15 as a potential regulator of the innate immune response. Braz J Med Biol Res. 1998;31(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  24. Perera PY, et al. The role of interleukin-15 in inflammation and immune responses to infection: implications for its therapeutic use. Microbes Infect. 2012;14(3):247–61.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang C, et al. Interleukin-15 improves cytotoxicity of natural killer cells via up-regulating NKG2D and cytotoxic effector molecule expression as well as STAT1 and ERK1/2 phosphorylation. Cytokine. 2008;42(1):128–36.

    Article  CAS  PubMed  Google Scholar 

  26. Treusch M, et al. Influence of human recombinant interferon-alpha2a (rhIFN-alpha2a) on altered lymphocyte subpopulations and monocytes in Behcet’s disease. Rheumatology (Oxford). 2004;43(10):1275–82.

    Article  CAS  Google Scholar 

  27. Suzuki Y, et al. Increased peripheral blood gamma delta+ T cells and natural killer cells in Behcet’s disease. J Rheumatol. 1992;19(4):588–92.

    CAS  PubMed  Google Scholar 

  28. Hasan MS, et al. Circulating NK cells and their subsets in Behcet’s disease. Clin Exp Immunol. 2017;188(2):311–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bonacini M, et al. Higher frequencies of lymphocytes expressing the natural killer group 2D receptor in patients with Behcet disease. Front Immunol. 2018;9:2157.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hamzaoui K, et al. Natural killer cells in Behcet’s disease. Clin Exp Immunol. 1988;71(1):126–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yamaguchi Y, et al. Natural killer cells control a T-helper 1 response in patients with Behcet’s disease. Arthritis Res Ther. 2010;12(3):R80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Kucuksezer UC, et al. Natural killer cells dominate a Th-1 polarized response in Behcet’s disease patients with uveitis. Clin Exp Rheumatol. 2015;33(6 Suppl 94):S24–9.

    PubMed  Google Scholar 

  33. Cosan F, et al. Natural killer cell subsets and their functional activity in Behcet’s disease. Immunol Invest. 2017;46(4):419–32.

    Article  CAS  PubMed  Google Scholar 

  34. Hamzaoui K, et al. Levels of IL-15 in serum and cerebrospinal fluid of patients with Behcet’s disease. Scand J Immunol. 2006;64(6):655–60.

    Article  CAS  PubMed  Google Scholar 

  35. Choe JY, et al. The distinct expressions of interleukin-15 and interleukin-15 receptor alpha in Behcet’s disease. Rheumatol Int. 2013;33(8):2109–15.

    Article  CAS  PubMed  Google Scholar 

  36. Curnow SJ, et al. Serum cytokine profiles in Behcet’s disease: is there a role for IL-15 in pathogenesis? Immunol Lett. 2008;121(1):7–12.

    Article  CAS  PubMed  Google Scholar 

  37. Gholijani N, et al. An elevated pro-inflammatory cytokines profile in Behcet’s disease: a multiplex analysis. Immunol Lett. 2017;186:46–51.

    Article  CAS  PubMed  Google Scholar 

  38. French AR, et al. IL-18 acts synergistically with IL-15 in stimulating natural killer cell proliferation. Cytokine. 2006;35(5–6):229–34.

    Article  CAS  PubMed  Google Scholar 

  39. Cany J, et al. Combined IL-15 and IL-12 drives the generation of CD34(+)-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer. Oncoimmunology. 2015;4(7):e1017701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet. 1990;335(8697):1078–80.

  41. Aktas E, et al. Relationship between CD107a expression and cytotoxic activity. Cell Immunol. 2009;254(2):149–54.

    Article  CAS  PubMed  Google Scholar 

  42. Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunol Res. 2015;3(6):575–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Billadeau DD, et al. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat Immunol. 2003;4(6):557–64.

    Article  CAS  PubMed  Google Scholar 

  44. Groh V, et al. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2003;100(16):9452–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Allez M, et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology. 2007;132(7):2346–58.

    Article  CAS  PubMed  Google Scholar 

  46. Clemente A, et al. Phenotype markers and cytokine intracellular production by CD8+ gammadelta T lymphocytes do not support a regulatory T profile in Behcet’s disease patients and healthy controls. Immunol Lett. 2010;129(2):57–63.

    Article  CAS  PubMed  Google Scholar 

  47. Rodacki M, et al. Altered natural killer cells in type 1 diabetic patients. Diabetes. 2007;56(1):177–85.

    Article  CAS  PubMed  Google Scholar 

  48. Tahrali I, et al. CD3(-)CD56(+) NK cells display an inflammatory profile in RR-MS patients. Immunol Lett. 2019;216:63–9.

    Article  CAS  PubMed  Google Scholar 

  49. Nielsen N, et al. Cytotoxicity of CD56(bright) NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A. PLoS ONE. 2012;7(2):e31959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ferlazzo G, et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med. 2002;195(3):343–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lin SJ, et al. Activating and inhibitory receptors on natural killer cells in patients with systemic lupus erythematosis-regulation with interleukin-15. PLoS ONE. 2017;12(10):e0186223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Thoren FB, et al. Human NK cells induce neutrophil apoptosis via an NKp46-and Fas-dependent mechanism. J Immunol. 2012;188(4):1668–74.

    Article  CAS  PubMed  Google Scholar 

  53. Sheppard S, et al. The murine natural cytotoxic receptor NKp46/NCR1 controls TRAIL protein expression in NK Cells and ILC1s. Cell Rep. 2018;22(13):3385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fujimori K, et al. Circulating neutrophils in Behcet disease is resistant for apoptotic cell death in the remission phase of uveitis. Graefes Arch Clin Exp Ophthalmol. 2008;246(2):285–90.

    Article  PubMed  Google Scholar 

  55. Cebrian M, et al. Triggering of T-cell proliferation through aim, an activation inducer molecule expressed on activated human-lymphocytes. J Exp Med. 1988;168(5):1621–37.

    Article  CAS  PubMed  Google Scholar 

  56. Sancho D, et al. CD69 downregulates autoimmune reactivity through active transforn ing growth factor-beta production in collagen-induced arthritis. J Clin Investig. 2003;112(6):872–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gonzalez-Amaro R, et al. Is CD69 an effective brake to control inflammatory diseases? Trends Mol Med. 2013;19(10):625–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Han YM, et al. CD69(+)CD4(+)CD25(-) T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immunol. 2009;182(1):111–20.

    Article  CAS  PubMed  Google Scholar 

  59. Rodriguez-Munoz A, et al. Levels of regulatory T cells CD69(+)NKG2D(+)IL-10(+) are increased in patients with autoimmune thyroid disorders. Endocrine. 2016;51(3):478–89.

    Article  CAS  PubMed  Google Scholar 

  60. Vitales-Noyola M, et al. Patients with systemic lupus erythematosus show increased levels and defective function of CD69(+) T regulatory cells. Mediators Inflamm. 2017;2017:2513829.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Vitales-Noyola M, et al. Quantitative and functional analysis of CD69(+) T regulatory lymphocytes in patients with periodontal disease. J Oral Pathol Med. 2017;46(7):549–57.

    Article  CAS  PubMed  Google Scholar 

  62. Rus V, et al. Increased expression and production of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) by T cells from lupus patients is a feature of active disease. Clin Immunol. 2005;115:S120–S120.

    Google Scholar 

  63. Onder M, B.M., Gürer MA, Gülekon A, Sezgin P, Imir T, Natural cellular cytotoxicity in Behçet’s disease. J Dermatol. 1994;4(Apr;21):239–43.

  64. Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294(1–2):15–22.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by Scientific Research Projects Coordination Unit (BAP) of Istanbul University (Project Numbers: 33564, 43303).

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  1. Nilgun Sallakci and Ilhan Tahrali have equally contributed to this work

Authors and Affiliations

  1. Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Vakif Gureba St. 34093, Istanbul, Turkey

    Nilgun Sallakci, Ilhan Tahrali, Umut Can Kucuksezer, Esin Aktas Cetin & Gunnur Deniz

  2. Faculty of Medicine, Genetic Laboratory, Akdeniz University, Antalya, Turkey

    Nilgun Sallakci

  3. Istanbul Faculty of Medicine, Department of Rheumatology, Istanbul University, Istanbul, Turkey

    Ahmet Gul

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  1. Nilgun Sallakci
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  2. Ilhan Tahrali
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Correspondence to Gunnur Deniz.

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Sallakci, N., Tahrali, I., Kucuksezer, U.C. et al. Effect of different cytokines in combination with IL-15 on the expression of activating receptors in NK cells of patients with Behçet’s disease. Immunol Res 70, 654–666 (2022). https://doi.org/10.1007/s12026-022-09298-5

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