Skip to main content

Advertisement

SpringerLink
Log in

MALT1 Protease Regulates T-Cell Immunity via the mTOR Pathway in Oral Lichen Planus

  • RESEARCH
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Oral lichen planus (OLP) is a T cell–mediated immune mucosal disease of unknown pathogenesis. Whether mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), an intracellular signaling protein, is involved in the T-cell immune dysfunction of OLP remains elusive. MALT1 expression in local and peripheral T cells of OLP and controls was analyzed using immunohistochemistry, multiplex immunohistochemistry, and flow cytometry. The expression of MALT1 in activated Jurkat T cells incubated with either OLP plasma or interleukin (IL)-7/IL-15 was determined by flow cytometry. The effects of MALT1 and mechanistic target of rapamycin (mTOR) on T-cell immunity were investigated through western blot, CCK8 assay, and flow cytometry. The expression of MALT1 protein was elevated in local OLP T cells and mucosal-associated invariant T (MAIT) cells, while reduced in peripheral OLP T cells, MAIT cells, and follicular helper-like MAIT (MAITfh) cells. Stimulation with OLP plasma and IL-7/ IL-15 had no effect on MALT1 expression in activated Jurkat T cells. MALT1 protease-specific inhibitor (MI-2) induced mTOR phosphorylation, increased B-cell lymphoma 10 (BCL10) expression, inhibited T-cell proliferation, and promoted T-cell apoptosis. The combination of MI-2 and rapamycin increased MALT1 expression, further suppressed T-cell proliferation, and facilitated T-cell apoptosis. MALT1 expression is aberrant in both local lesions and peripheral blood of OLP. Inhibition of the mTOR pathway further enhances the suppression of T-cell proliferation and the promotion of apoptosis induced by the MALT1 inhibitor MI-2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Availability of Data and Materials

The data supporting the conclusions of this article are available from the corresponding author upon reasonable request.

References

  1. El-Howati, A., M.H. Thornhill, H.E. Colley, and C. Murdoch. 2023. Immune mechanisms in oral lichen planus. Oral Diseases 29: 1400–1415. https://doi.org/10.1111/odi.14142.

    Article  PubMed  Google Scholar 

  2. González-Moles, M., S. Warnakulasuriya, I. González-Ruiz, L. González-Ruiz, et al. 2021. Worldwide prevalence of oral lichen planus: A systematic review and meta-analysis. Oral Diseases 27: 813–828. https://doi.org/10.1111/odi.13323.

    Article  PubMed  Google Scholar 

  3. Deng, X., Y. Wang, L. Jiang, J. Li, et al. 2022. Updates on immunological mechanistic insights and targeting of the oral lichen planus microenvironment. Frontiers in Immunology 13: 1023213. https://doi.org/10.3389/fimmu.2022.1023213.

    Article  PubMed  CAS  Google Scholar 

  4. Didona, D., and M. Hertl. 2022. Detection of anti-desmoglein antibodies in oral lichen planus: What do we know so far. Frontiers in Immunology 13: 1001970. https://doi.org/10.3389/fimmu.2022.1001970.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Roopashree, M.R., R.V. Gondhalekar, M.C. Shashikanth, J. George, et al. 2010. Pathogenesis of oral lichen planus–a review. Journal of Oral Pathology and Medicine 39: 729–734. https://doi.org/10.1111/j.1600-0714.2010.00946.x.

    Article  PubMed  CAS  Google Scholar 

  6. Takimoto, T., S. Maegawa, H. Tatsumi, H. Nagoshi, et al. 2017. Extranodal marginal zone lymphoma of the uterine cervix with concomitant copy number gains of the MALT1 and BCL2 genes: A case report. Oncology Letters 13: 3641–3645. https://doi.org/10.3892/ol.2017.5944.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Gu H, Zheng S, Han G, Yang H et al. 2022. Porcine reproductive and respiratory syndrome virus adapts antiviral innate immunity via manipulating MALT1. mBio 13: e0066422. https://doi.org/10.1128/mbio.00664-22.

  8. Demeyer, A., J. Staal, and R. Beyaert. 2016. Targeting MALT1 proteolytic activity in immunity, inflammation and disease: Good or bad? Trends in Molecular Medicine 22: 135–150. https://doi.org/10.1016/j.molmed.2015.12.004.

    Article  PubMed  CAS  Google Scholar 

  9. Ginster, S., M. Bardet, A. Unterreiner, C. Malinverni, et al. 2017. Two antagonistic MALT1 auto-cleavage mechanisms reveal a role for TRAF6 to unleash MALT1 activation. PLoS ONE 12: e0169026. https://doi.org/10.1371/journal.pone.0169026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mempel TR, Krappmann D. 2022. Combining precision oncology and immunotherapy by targeting the MALT1 protease.  Journal for ImmunoTherapy of Cancer 10. https://doi.org/10.1136/jitc-2022-005442.

  11. Hamilton KS, Phong B, Corey C, Cheng J et al. 2014. T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Science Signaling 7: ra55. https://doi.org/10.1126/scisignal.2005169.

  12. Nakaya, M., Y. Xiao, X. Zhou, J.H. Chang, et al. 2014. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40: 692–705. https://doi.org/10.1016/j.immuni.2014.04.007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Wang, F., J. Zhang, and G. Zhou. 2020. The mTOR-glycolytic pathway promotes T-cell immunobiology in oral lichen planus. Immunobiology 225: 151933. https://doi.org/10.1016/j.imbio.2020.151933.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang, N., J. Zhang, Y.Q. Tan, G.F. Du, et al. 2017. Activated Akt/mTOR-autophagy in local T cells of oral lichen planus. International Immunopharmacology 48: 84–90. https://doi.org/10.1016/j.intimp.2017.04.016.

    Article  PubMed  CAS  Google Scholar 

  15. O’Neill, T.J., A. Gewies, T. Seeholzer, and D. Krappmann. 2023. TRAF6 controls T cell homeostasis by maintaining the equilibrium of MALT1 scaffolding and protease functions. Frontiers in Immunology 14: 1111398. https://doi.org/10.3389/fimmu.2023.1111398.

  16. Salou, M., K. Franciszkiewicz, and O. Lantz. 2017. MAIT cells in infectious diseases. Current Opinion in Immunology 48: 7–14. https://doi.org/10.1016/j.coi.2017.07.009.

    Article  PubMed  CAS  Google Scholar 

  17. Lu, H.Y., C.M. Biggs, G. Blanchard-Rohner, S.Y. Fung, et al. 2019. Germline CBM-opathies: From immunodeficiency to atopy. The Journal of Allergy and Clinical Immunology 143: 1661–1673. https://doi.org/10.1016/j.jaci.2019.03.009.

    Article  PubMed  Google Scholar 

  18. Jensen O, Trivedi S, Meier JD, Fairfax KC et al. 2022. A subset of follicular helper-like MAIT cells can provide B cell help and support antibody production in the mucosa. Sci Immunol. 7: eabe8931. https://doi.org/10.1126/sciimmunol.abe8931.

  19. Yang, J.Y., F. Wang, and G. Zhou. 2022. Characterization and function of circulating mucosal-associated invariant T cells and γδT cells in oral lichen planus. Journal of Oral Pathology and Medicine 51: 74–85. https://doi.org/10.1111/jop.13250.

    Article  PubMed  CAS  Google Scholar 

  20. Tan, Y.Q., Q. Li, J. Zhang, G.F. Du, et al. 2017. Increased circulating CXCR5(+) CD4(+) T follicular helper-like cells in oral lichen planus. Journal of Oral Pathology and Medicine 46: 803–809. https://doi.org/10.1111/jop.12550.

    Article  PubMed  CAS  Google Scholar 

  21. Warnakulasuriya, S., O. Kujan, J.M. Aguirre-Urizar, J.V. Bagan, et al. 2021. Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer. Oral Diseases 27: 1862–1880. https://doi.org/10.1111/odi.13704.

    Article  PubMed  Google Scholar 

  22. Peng, Q., J. Zhang, and G. Zhou. 2019. Circulating exosomes regulate T-cell-mediated inflammatory response in oral lichen planus. Journal of Oral Pathology and Medicine 48: 143–150. https://doi.org/10.1111/jop.12804.

    Article  PubMed  CAS  Google Scholar 

  23. Zhou, G., J. Zhang, X.W. Ren, J.Y. Hu, et al. 2012. Increased B7–H1 expression on peripheral blood T cells in oral lichen planus correlated with disease severity. Journal of Clinical Immunology 32: 794–801. https://doi.org/10.1007/s10875-012-9683-2.

    Article  PubMed  CAS  Google Scholar 

  24. Ruland, J., and L. Hartjes. 2019. CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nature Reviews Immunology 19: 118–134. https://doi.org/10.1038/s41577-018-0087-2.

    Article  PubMed  CAS  Google Scholar 

  25. Jaworski, M., and M. Thome. 2016. The paracaspase MALT1: Biological function and potential for therapeutic inhibition. Cellular and Molecular Life Sciences 73: 459–473. https://doi.org/10.1007/s00018-015-2059-z.

    Article  PubMed  CAS  Google Scholar 

  26. Liu, L., Y. Gao, Y. Si, B. Liu, et al. 2022. MALT1 in asthma children: A potential biomarker for monitoring exacerbation risk and Th1/Th2 imbalance-mediated inflammation. Journal of Clinical Laboratory Analysis 36: e24379. https://doi.org/10.1002/jcla.24379.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Wu, Z., and Y. Bi. 2022. Potential role of MALT1 as a candidate biomarker of disease surveillance and treatment response prediction in inflammatory bowel disease patients. Journal of Clinical Laboratory Analysis 36: e24130. https://doi.org/10.1002/jcla.24130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Wang, F., J. Zhang, and G. Zhou. 2019. Deregulated phospholipase D2/mammalian target of rapamycin/hypoxia-inducible factor 1 alpha in peripheral T lymphocytes of oral lichen planus correlated with disease severity. Archives of Oral Biology 98: 26–31. https://doi.org/10.1016/j.archoralbio.2018.11.003.

    Article  PubMed  CAS  Google Scholar 

  29. Bell, P.A., S. Scheuermann, F. Renner, C.L. Pan, et al. 2022. Integrating knowledge of protein sequence with protein function for the prediction and validation of new MALT1 substrates. Computational and Structural Biotechnology Journal 20: 4717–4732. https://doi.org/10.1016/j.csbj.2022.08.021.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Xia, X., G. Cao, G. Sun, L. Zhu, et al. 2020. GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis. The Journal of Clinical Investigation 130: 5180–5196. https://doi.org/10.1172/jci129269.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rosebeck, S., A.O. Rehman, P.C. Lucas, and L.M. McAllister-Lucas. 2011. From MALT lymphoma to the CBM signalosome: Three decades of discovery. Cell Cycle 10: 2485–2496. https://doi.org/10.4161/cc.10.15.16923.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Yang, J.G., Y.R. Sun, G.Y. Chen, X.Y. Liang, et al. 2016. Different expression of microRNA-146a in peripheral blood CD4(+) T cells and lesions of oral lichen planus. Inflammation 39: 860–866. https://doi.org/10.1007/s10753-016-0316-4.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang, J., M.H. Wei, R. Lu, G.F. Du, et al. 2016. Declined hTERT expression of peripheral blood CD4(+) T cells in oral lichen planus correlated with clinical parameter. Journal of Oral Pathology and Medicine 45: 516–522. https://doi.org/10.1111/jop.12399.

    Article  PubMed  CAS  Google Scholar 

  34. O’Flatharta, C., M. Leader, E. Kay, S.R. Flint, et al. 2002. Telomerase activity detected in oral lichen planus by RNA in situ hybridisation: Not a marker for malignant transformation. Journal of Clinical Pathology 55: 602–607. https://doi.org/10.1136/jcp.55.8.602.

  35. Wang, Z.M., J. Zhang, F. Wang, and G. Zhou. 2021. The tipped balance of ILC1/ILC2 in peripheral blood of oral lichen planus is related to inflammatory cytokines. Front Cell Dev Biol. 9: 725169. https://doi.org/10.3389/fcell.2021.725169.

    Article  PubMed  Google Scholar 

  36. Yang, J.Y., Y.Q. Tan, and G. Zhou. 2022. T cell-derived exosomes containing cytokines induced keratinocytes apoptosis in oral lichen planus. Oral Diseases 28: 682–690. https://doi.org/10.1111/odi.13795.

    Article  PubMed  Google Scholar 

  37. Wang, C.J., Y.J. Li, J.N. Xue, H.S. Ci, et al. 2016. Correlation of Treg and IL-15 expression in the peripheral blood of patients with oral lichen planus. Shanghai Kou Qiang Yi Xue. 25: 438–442.

    PubMed  Google Scholar 

  38. Lu, R., J. Zhang, W. Sun, G. Du, et al. 2015. Inflammation-related cytokines in oral lichen planus: An overview. Journal of Oral Pathology and Medicine 44: 1–14. https://doi.org/10.1111/jop.12142.

    Article  PubMed  CAS  Google Scholar 

  39. Schmitt, A., P. Grondona, T. Maier, M. Brändle, et al. 2016. MALT1 protease activity controls the expression of inflammatory genes in keratinocytes upon zymosan stimulation. The Journal of Investigative Dermatology 136: 788–797. https://doi.org/10.1016/j.jid.2015.12.027.

    Article  PubMed  CAS  Google Scholar 

  40. de Koning, H.D., D. Rodijk-Olthuis, I.M. van Vlijmen-Willems, L.A. Joosten, et al. 2010. A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: Upregulation of dectin-1 in psoriasis. The Journal of Investigative Dermatology 130: 2611–2620. https://doi.org/10.1038/jid.2010.196.

    Article  PubMed  CAS  Google Scholar 

  41. Zhou, G., K. Xia, G.F. Du, X.M. Chen, et al. 2009. Activation of nuclear factor-kappa B correlates with tumor necrosis factor-alpha in oral lichen planus: A clinicopathologic study in atrophic-erosive and reticular form. Journal of Oral Pathology and Medicine 38: 559–564. https://doi.org/10.1111/j.1600-0714.2009.00779.x.

    Article  PubMed  CAS  Google Scholar 

  42. Hu, J.Y., J. Zhang, J.L. Cui, X.Y. Liang, et al. 2013. Increasing CCL5/CCR5 on CD4+ T cells in peripheral blood of oral lichen planus. Cytokine 62: 141–145. https://doi.org/10.1016/j.cyto.2013.01.020.

    Article  PubMed  CAS  Google Scholar 

  43. Ge X, Xie H, Nguyen T, Zhao B et al. 2020. Renin promotes STAT4 phosphorylation to induce IL-17 production in keratinocytes of oral lichen planus. iScience. 23: 100983. https://doi.org/10.1016/j.isci.2020.100983.

  44. Marshall, A., A. Celentano, N. Cirillo, M. McCullough, et al. 2017. Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease. PLoS ONE 12: e0172821. https://doi.org/10.1371/journal.pone.0172821.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Zhang, Q., S. Zhang, H. Chen, G. Chen, et al. 2023. Targeting of MALT1 may improve functional recovery and attenuate microglia M1 polarization-mediated neuroinflammation during spinal cord injury. Molecular Neurobiology 60: 2632–2643. https://doi.org/10.1007/s12035-023-03208-y.

    Article  PubMed  CAS  Google Scholar 

  46. Bornancin, F., F. Renner, R. Touil, H. Sic, et al. 2015. Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. The Journal of Immunology 194: 3723–3734. https://doi.org/10.4049/jimmunol.1402254.

    Article  PubMed  CAS  Google Scholar 

  47. Santulli, G., and H. Totary-Jain. 2013. Tailoring mTOR-based therapy: Molecular evidence and clinical challenges. Pharmacogenomics 14: 1517–1526. https://doi.org/10.2217/pgs.13.143.

    Article  PubMed  CAS  Google Scholar 

  48. Ruland, J. 2021. Synergy of MALT1 and mTOR inhibition in DLBCL. Blood 137: 724–725. https://doi.org/10.1182/blood.2020008465.

    Article  PubMed  CAS  Google Scholar 

  49. Tahiliani, V., T.E. Hutchinson, G. Abboud, M. Croft, et al. 2017. OX40 Cooperates with ICOS to amplify follicular Th cell development and germinal center reactions during infection. The Journal of Immunology 198: 218–228. https://doi.org/10.4049/jimmunol.1601356.

    Article  PubMed  CAS  Google Scholar 

  50. Lu, R., G. Zhou, G. Du, X. Xu, et al. 2011. Expression of T-bet and GATA-3 in peripheral blood mononuclear cells of patients with oral lichen planus. Archives of Oral Biology 56: 499–505. https://doi.org/10.1016/j.archoralbio.2010.11.006.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was supported by grants from National Natural Science Foundation of China (No. 81970949 and No. 82270983).

Author information

Authors and Affiliations

  1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China

    Xiao-Feng Wang, Fang Wang & Gang Zhou

  2. Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University, Luoyu Road 237, Wuhan, 430079, China

    Fang Wang & Gang Zhou

Authors
  1. Xiao-Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XW performed the experiments, analyzed the data, and drafted the manuscript. FW conceived the study and revised the manuscript. GZ conceived the study, supervised the experiments, and provided the resources. All authors have read and approved the final article.

Corresponding author

Correspondence to Gang Zhou.

Ethics declarations

Ethics Approval

This study was approved by the Ethics Committee of the School and Hospital of Stomatology, Wuhan University (No. 2019A17), and was conducted in compliance with the ethical guidelines of the Declaration of Helsinki.

Consent to Participate

Informed consent was obtained from all subjects.

Consent for Publication

Informed consent for publication was obtained from all subjects.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 442 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, XF., Wang, F. & Zhou, G. MALT1 Protease Regulates T-Cell Immunity via the mTOR Pathway in Oral Lichen Planus. Inflammation (2023). https://doi.org/10.1007/s10753-023-01952-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10753-023-01952-w

KEY WORDS

Search

Navigation