Top

Published in:

Open Access 01-12-2024 | Kawasaki Disease | Review

Immunomodulatory effects of iTr35 cell subpopulation and its research progress

Authors: Chenxi Yang, Lingli Dong, Jixin Zhong

Published in: Clinical and Experimental Medicine | Issue 1/2024

Abstract

The spotlight in recent years has increasingly focused on inducible regulatory T cells 35 (iTr35), a novel subpopulation of regulatory T cells characterized by phenotypic stability, heightened reactivity, and potent immunosuppressive function through the production of IL-35. Despite being in the exploratory phase, research on iTr35 has garnered significant interest. In this review, we aim to consolidate our understanding of the biological characteristics and immunomodulatory mechanisms of iTr35, offering fresh perspectives that may pave the way for its potential applications in disease diagnosis and treatment.

Pillai MR, Collison LW, Wang X, et al. The plasticity of regulatory T cell function. J Immunol. 2011;187(10):4987–97. https://doi.org/10.4049/jimmunol.1102173.CrossRefPubMed

Tomcik M, Zerr P, Palumbo-Zerr K, et al. Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease. Rheumatology (Oxford). 2015;54(12):2273–82. https://doi.org/10.1093/rheumatology/kev260.CrossRefPubMed

Zhu JJ, Shan NN. Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia. J Int Med Res. 2020;48(12):1–13. https://doi.org/10.1177/0300060520976477.CrossRef

Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, Liew FY. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007;37(11):3021–9. https://doi.org/10.1002/eji.200737810.CrossRefPubMed

Bettini M, Vignali DA. Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol. 2009;21(6):612–8. https://doi.org/10.1016/j.coi.2009.09.011.CrossRefPubMedPubMedCentral

Chaturvedi V, Collison LW, Guy CS, et al. Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol. 2011;186:6661–6. https://doi.org/10.4049/jimmunol.1100315.CrossRefPubMed

Collison LW, Chaturvedi V, Henderson AL, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11(12):1093–101. https://doi.org/10.1038/ni.1952.CrossRefPubMedPubMedCentral

Yang C, Lei L, Pan J, Zhao C, Wen J, Qin F, Dong F, Wei W. Altered CD4+ T cell and cytokine levels in peripheral blood and skin samples from systemic sclerosis patients and IL-35 in CD4+ T cell growth. Rheumatology (Oxford). 2022;61(2):794–805. https://doi.org/10.1093/rheumatology/keab359.CrossRefPubMed

Yang C, Lu C, Pan J, Zhao C, Chen Z, Qin F, Wen J, Wei W, Lei L. The role of iTr35 cells in the inflammatory response and fibrosis progression of systemic sclerosis. Rheumatology (Oxford). 2023. https://doi.org/10.1093/rheumatology/kead053.CrossRefPubMedPubMedCentral

10.

Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8(7):523–32. https://doi.org/10.1038/nri2343.CrossRefPubMedPubMedCentral

11.

Arce-Sillas A, Álvarez-Luquín DD, Tamaya-Domínguez B, et al. Regulatory T cells: molecular actions on effector cells in immune regulation. J Immunol Res. 2016;2016:1720827. https://doi.org/10.1155/2016/1720827.CrossRefPubMedPubMedCentral

12.

Lloyd CM, Hawrylowicz CM. Regulatory T cells in asthma. Immunity. 2009;31(3):438–49. https://doi.org/10.1016/j.immuni.2009.08.007.CrossRefPubMedPubMedCentral

13.

Dons EM, Raimondi G, Cooper DK, et al. Induced regulatory T cells: mechanisms of conversion and suppressive potential. Hum Immunol. 2012;73(4):328–34. https://doi.org/10.1016/j.humimm.2011.12.011.CrossRefPubMedPubMedCentral

14.

Foss CA, Kulik L, Ordonez AA, et al. SPECT/CT Imaging of mycobacterium tuberculosis infection with [I]anti-C3d mAb. Mol Imaging Biol. 2019;21(3):473–81. https://doi.org/10.1007/s11307-018-1228-5.CrossRefPubMedPubMedCentral

15.

Yu F, Zhu X, Li Q, et al. Mycobacterium tuberculosis elevated IL-35 level and iTr35 subset increases the bacterial burden and lung lesions in -infected mice. Open Life Sci. 2022;17(1):312–20. https://doi.org/10.1515/biol-2022-0025.CrossRefPubMedPubMedCentral

16.

Katelaris CH, Lee BW, Potter PC, et al. Prevalence and diversity of allergic rhinitis in regions of the world beyond Europe and North America. Clin Exp Allergy. 2012;42(2):186–207. https://doi.org/10.1111/j.1365-2222.2011.03891.x.CrossRefPubMed

17.

Shamji MH, Layhadi JA, Achkova D, et al. Role of IL-35 in sublingual allergen immunotherapy. J Allergy Clin Immunol. 2019;143(3):1131-1142.e4. https://doi.org/10.1016/j.jaci.2018.06.041.CrossRefPubMed

18.

Layhadi JA, Eguiluz-Gracia I, Shamji MH. Role of IL-35 in sublingual allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2019;19(1):12–7. https://doi.org/10.1097/ACI.0000000000000499.CrossRefPubMed

19.

Liu W, Zeng Q, Wen Y, et al. Inhibited interleukin 35 expression and interleukin 35-induced regulatory T cells promote type II innate lymphoid cell response in allergic rhinitis [J]. Ann Allergy Asthma Immunol. 2021;126(2):152-161.e1. https://doi.org/10.1016/j.anai.2020.08.005.CrossRefPubMed

20.

Wei W, Ping Li, Yi-fei C, et al. A potential immunopathogenic role for reduced IL-35 expression in allergic asthma. J Asthma. 2015;52:763–71.CrossRef

21.

Wang W, Wei C, Cheng Z, et al. Aberrant Th2 immune responses are associated with a reduced frequency of IL-35-induced regulatory T cells after allergen exposure in patients with allergic asthma. Allergy Asthma Immunol Res. 2020;12(6):1029–45. https://doi.org/10.4168/aair.2020.12.6.1029.CrossRefPubMedPubMedCentral

22.

Sun A, Wu YH, Chang JYF, et al. FoxP3CD4, IFN-γCD4, and IFN-γCD8 cell levels in erosive and non-erosive types of oral lichen planus patients. J Dent Sci. 2021;16(2):751–6. https://doi.org/10.1016/j.jds.2021.01.005.CrossRefPubMedPubMedCentral

23.

Zheng L, Jia P, Cai Y. Distribution ratio and significance of iTr35 cells in peripheral blood of patients with oral lichen planus. Oral Med Res. 2022;38(1):76–9. https://doi.org/10.13701/j.cnki.kqyxyj.2022.01.016.CrossRef

24.

Greco A, De Virgilio A, Rizzo MI, et al. Kawasaki disease: an evolving paradigm. Autoimmun Rev. 2015;14(8):703–9. https://doi.org/10.1016/j.autrev.2015.04.002.CrossRefPubMed

25.

Zhao JS, Wang Q, Wen PQ, et al. Altered IL-35 regulatory T lymphocyte subpopulations and significance in children with Kawasaki disease in the acute phase. Chin Clin J Pract Pediatr. 2016;31(09):662–6.

26.

Dantas AT, Gonçalves SM, Pereira MC, et al. Increased IL-35 serum levels in systemic sclerosis and association with pulmonary interstitial involvement. Clin Rheumatol. 2015;34(9):1621–5. https://doi.org/10.1007/s10067-015-3006-y.CrossRefPubMed

27.

Yayla ME, Torgutalp M, Okatan İE, et al. Serum interleukin 35 levels in systemic sclerosis and relationship with clinical features. J Clin Rheumatol. 2020;26(3):83–6. https://doi.org/10.1097/RHU.0000000000000947.CrossRefPubMed

28.

Cui Y, Wang W, Dong N, et al. Role of Corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature. 2012;484(7393):246–50. https://doi.org/10.1038/nature10897.ADSCrossRefPubMedPubMedCentral

29.

Mercy PrabhuDas, Elizabeth B, Kathleen C, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol. 2015;16:328–34. https://doi.org/10.1038/ni.3131.CrossRef

30.

Chen SJ, Liu YL, Sytwu HK. Immunologic regulation in pregnancy: from mechanism to therapeutic strategy for immunomodulation. Clin Dev Immunol. 2012. https://doi.org/10.1155/2012/258391.CrossRefPubMedPubMedCentral

31.

Du MR, Guo PF, Piao HL, et al. Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal-fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells. J Immunol. 2014;192(4):1502–11. https://doi.org/10.4049/jimmunol.1203425.CrossRefPubMedPubMedCentral

32.

Liu J, Hao S, Chen X, et al. Human placental trophoblast cells contribute to maternal-fetal tolerance through expressing IL-35 and mediating iT35 conversion. Nat Commun. 2019;10(1):4601. https://doi.org/10.1038/s41467-019-12484-z.ADSCrossRefPubMedPubMedCentral

33.

Xu WC, Huang YM, Xiao HF. Serum interleukin-35 expression level and its induced production of novel regulatory T cells iTR35 ratio and clinical significance in patients with myelodysplastic syndrome [J]. Chin J Exp Hematol. 2017;25(01):157–63.

34.

Wang LH, Wang GB, Wen FQ, et al. Preliminary investigation on the alteration and significance of iTR35 regulatory T cell subpopulation in acute B precursor lymphocytic leukemia in children. Chin J Evid Based Pediatr. 2015;10(03):227–31.

35.

Tao Q, Pan Y, Wang Y, et al. Regulatory T cells-derived IL-35 promotes the growth of adult acute myeloid leukemia blasts. Int J Cancer. 2015;137(10):2384–93. https://doi.org/10.1002/ijc.29563.CrossRefPubMed

36.

Le Gouvello S, Bastuji-Garin S, Aloulou N, et al. High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut. 2008;57(6):772–9. https://doi.org/10.1136/gut.2007.123794.CrossRefPubMed

37.

Ling KL, Pratap SE, Bates GJ, et al. Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun. 2007;7:7.PubMedPubMedCentral

38.

Michel S, Benner A, Tariverdian M, et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008;99(11):1867–73. https://doi.org/10.1038/sj.bjc.6604756.CrossRefPubMedPubMedCentral

39.

Ma Y, Chen L, Xie G, et al. Elevated level of interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3. Oncotarget. 2016;7(45):73003–15. https://doi.org/10.18632/oncotarget.12193.CrossRefPubMedPubMedCentral

40.

Ma R, Feng Y, Lin S, et al. Mechanisms involved in breast cancer liver metastasis. J Transl Med. 2015;13:64. https://doi.org/10.1186/s12967-015-0425-0.CrossRefPubMedPubMedCentral

41.

Oleinika K, Nibbs RJ, Graham GJ, et al. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013;171(1):36–45. https://doi.org/10.1111/j.1365-2249.2012.04657.x.CrossRefPubMed

42.

Zhao Z, Chen X, Hao S, et al. Increased interleukin-35 expression in tumor-infiltrating lymphocytes correlates with poor prognosis in patients with breast cancer. Cytokine. 2017;89:76–81. https://doi.org/10.1016/j.cyto.2016.09.012.CrossRefPubMed

43.

Hao S, Chen X, Wang F, et al. Breast cancer cell-derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells. Carcinogenesis. 2018;39(12):1488–96. https://doi.org/10.1093/carcin/bgy136.CrossRefPubMed

44.

Huang C, Li N, Li Z, et al. Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression. Nat Commun. 2017;8:14035. https://doi.org/10.1038/ncomms14035.MathSciNetCrossRefPubMedPubMedCentral

45.

Liang Y, Chen Q, Du W, et al. Epstein-barr virus-induced gene 3 (EBI3) blocking leads to induce antitumor cytotoxic T lymphocyte response and suppress tumor growth in colorectal cancer by bidirectional reciprocal-regulation STAT3 signaling pathway. Mediators Inflamm. 2016;2016:3214105. https://doi.org/10.1155/2016/3214105.CrossRefPubMedPubMedCentral

46.

Fu YP, Yi Y, Cai XY, et al. Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection. Br J Cancer. 2016;114(7):767–76. https://doi.org/10.1038/bjc.2016.47.CrossRefPubMedPubMedCentral

47.

Turnis ME, Sawant DV, Szymczak-Workman AL, et al. Interleukin-35 limits anti-tumor immunity. Immunity. 2016;44(2):316–29. https://doi.org/10.1016/j.immuni.2016.01.013.CrossRefPubMedPubMedCentral

48.

Park AC, Huang G, Jankowska-Gan E, et al. Mucosal administration of collagen V ameliorates the atherosclerotic plaque burden by inducing interleukin 35-dependent tolerance. J Biol Chem. 2016;291(7):3359–70. https://doi.org/10.1074/jbc.M115.681882.CrossRefPubMed

49.

Bobryshev YV, Sobenin IA, Orekhov AN, et al. Novel anti-inflammatory interleukin-35 as an emerging target for antiatherosclerotic therapy. Curr Pharm Des. 2015;21(9):1147–51. https://doi.org/10.2174/1381612820666141014123810.CrossRefPubMed

50.

Luo M, Peng H, Chen P, et al. The immunomodulatory role of interleukin-35 in fibrotic diseases. Expert Rev Clin Immunol. 2019;15(4):431–9. https://doi.org/10.1080/1744666X.2019.1564041.CrossRefPubMed

51.

Li N, Liu MY, Ma XM. Expression and clinical significance of peripheral blood iTr35 cells and their effector IL-35 in patients with idiopathic pulmonary fibrosis. Micronutr Health Res. 2022;39(3):11–3.

Title: Immunomodulatory effects of iTr35 cell subpopulation and its research progress
Authors: Chenxi Yang
Lingli Dong
Jixin Zhong
Publication date: 01-12-2024
Publisher: Springer International Publishing
Keywords: Kawasaki Disease
Kawasaki Disease
Kawasaki Disease
Cytokines
Published in: Clinical and Experimental Medicine / Issue 1/2024
Print ISSN: 1591-8890
Electronic ISSN: 1591-9528
DOI: https://doi.org/10.1007/s10238-024-01303-5

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.

Extracellular matrix protein 1 (ECM1) is a potential biomarker in B cell acute lymphoblastic leukemia

Longitudinal study of human polyomaviruses viruria in kidney transplant recipients

The demographic, laboratory and genetic factors associated with long Covid-19 syndrome: a case–control study

Treatment strategies in MDA5-positive clinically amyopathic dermatomyositis: a single-center retrospective analysis

Low platelet count at diagnosis of anti-neutrophil cytoplasmic antibody-associated vasculitis is correlated with the severity of disease and renal prognosis

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials