Skip to main content

Advertisement

SpringerLink
Log in

Rnf20 inhibition enhances immunotherapy by improving regulatory T cell generation

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Background

Allergic disorders are common all over the world. The pathogenesis of allergy is unclear. Therapies for allergic disorders require improvement. Endoplasmic reticulum (ER) stress is one of the factors influencing immune response. The purpose of this study is to improve the effectiveness of immunotherapy for experimental respiratory allergy by targeting the ER stress signal pathway.

Methods

Committed CD4+ T cells were isolated from blood samples collected from patients with allergic rhinitis (AR) and TCR ovalbumin transgenic mice. The effects of TCR engagement and 3-methyl-4-nitrophenol (MNP) on inducing ER stress in committed CD4+ T cells were evaluated.

Results

ER stress was detected in antigen-specific CD4+ T cells (sCD4+ T cells) of AR patients. The environmental pollutant MNP increased the expression of the X-binding protein-1 (XBP1) in the committed CD4+ T cells during the TCR engagement. XBP1 mediated the effects of MNP on inhibiting regulatory T cell (Treg) generation. The effects of MNP on induction of protein 20 (Rnf20) in CD4+ T cells were mediated by XBP1. Inhibition of Rnf20 rescued the Treg development from MNP-primed sCD4+ T cells. The ablation of Rnf20 improved the immunotherapy of AR through the restoration of the Treg generation.

Conclusions

ER stress can be detected in CD4+ T cells in TCR engagement. Exposure to MNP exacerbates ER stress in committed CD4+ T cells. Regulation of the ER stress-related Rnf20 expression can restore the generation of Treg from CD4+ T cells of subjects with allergic diseases.

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

Similar content being viewed by others

Data availability

All the data are included in this paper.

References

  1. Dominguez-Villar M, Hafler DA (2018) Regulatory T cells in autoimmune disease. Nat Immunol 19(7):665–673

    Article  CAS  Google Scholar 

  2. Tanoue T, Atarashi K, Honda K (2016) Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 16(5):295–309

    Article  CAS  Google Scholar 

  3. Oakes SA, Papa FR (2015) The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol 10:173–194

    Article  CAS  Google Scholar 

  4. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8(7):519–529

    Article  CAS  Google Scholar 

  5. Kaech SM, Wherry EJ, Ahmed R (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2(4):251–262

    Article  CAS  Google Scholar 

  6. Mims JW (2015) Asthma: definitions and pathophysiology. Int Forum Allergy Rhinol 5(Suppl 1):S2-6

    Article  Google Scholar 

  7. Tian GX, Peng KP, Liu MH, Tian DF, Xie HQ, Wang LW, Guo YY, Zhou S, Mo LH, Yang PC (2022) CD38(+) B cells affect immunotherapy for allergic rhinitis. J Allergy Clin Immunol 149(5):1691-1701.e9

    Article  CAS  Google Scholar 

  8. Pfistershammer K, Majdic O, Stöckl J, Zlabinger G, Kirchberger S, Steinberger P, Knapp W (2004) CD63 as an activation-linked T cell costimulatory element. J Immunol 173(10):6000–6008

    Article  CAS  Google Scholar 

  9. Pope CA 3rd, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, Thurston GD (2002) Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA 287(9):1132–1141

    Article  CAS  Google Scholar 

  10. Pope CA 3rd, Coleman N, Pond ZA, Burnett RT (2020) Fine particulate air pollution and human mortality: 25+ years of cohort studies. Environ Res 183:108924

    Article  CAS  Google Scholar 

  11. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107(7):881–891

    Article  CAS  Google Scholar 

  12. Cortez JT, Montauti E, Shifrut E, Gatchalian J, Zhang Y, Shaked O, Xu Y, Roth TL, Simeonov DR, Zhang Y, Chen S, Li Z, Woo JM, Ho J, Vogel IA, Prator GY, Zhang B, Lee Y, Sun Z, Ifergan I, Van Gool F, Hargreaves DC, Bluestone JA, Marson A, Fang D (2020) CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature 582(7812):416–420

    Article  CAS  Google Scholar 

  13. Wiegman CH, Michaeloudes C, Haji G, Narang P, Clarke CJ, Russell KE, Bao W, Pavlidis S, Barnes PJ, Kanerva J, Bittner A, Rao N, Murphy MP, Kirkham PA, Chung KF, Adcock IM (2015) Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 136(3):769–780

    Article  CAS  Google Scholar 

  14. Lee HY, Lee GH, Kim HK, Chae HJ (2019) Platycodi Radix and its active compounds ameliorate against house dust mite-induced allergic airway inflammation and ER stress and ROS by enhancing anti-oxidation. Food Chem Toxicol 123:412–423

    Article  CAS  Google Scholar 

  15. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415(6867):92–96

    Article  CAS  Google Scholar 

  16. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, Yu X, Yang L, Tan BK, Rosenwald A, Hurt EM, Petroulakis E, Sonenberg N, Yewdell JW, Calame K, Glimcher LH, Staudt LM (2004) XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21(1):81–93

    Article  CAS  Google Scholar 

  17. Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, Zhang S, Bettigole SE, Gupta D, Holcomb K, Ellenson LH, Caputo T, Lee AH, Conejo-Garcia JR, Glimcher LH (2015) ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161(7):1527–1538

    Article  CAS  Google Scholar 

  18. Song M, Sandoval TA, Chae CS, Chopra S, Tan C, Rutkowski MR, Raundhal M, Chaurio RA, Payne KK, Konrad C, Bettigole SE, Shin HR, Crowley MJP, Cerliani JP, Kossenkov AV, Motorykin I, Zhang S, Manfredi G, Zamarin D, Holcomb K, Rodriguez PC, Rabinovich GA, Conejo-Garcia JR, Glimcher LH, Cubillos-Ruiz JR (2018) IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562(7727):423–428

    Article  CAS  Google Scholar 

  19. Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, Greene S, Zeng Q, Fazli L, Rennie PS, Mills IG, Danielsen H, Theis F, Patterson JB, Jin Y, Saatcioglu F (2019) IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat Commun 10(1):323

    Article  CAS  Google Scholar 

  20. Mori Y, Kamata K, Toda N, Hayashi H, Seki K, Taneda S, Yoshino S, Sakushima A, Sakata M, Suzuki AK (2003) Isolation of nitrophenols from diesel exhaust particles (DEP) as vasodilatation compounds. Biol Pharm Bull 26(3):394–395

    Article  CAS  Google Scholar 

  21. Takeo M, Yamamoto K, Sonoyama M, Miyanaga K, Kanbara N, Honda K, Kato DI, Negoro S (2018) Characterization of the 3-methyl-4-nitrophenol degradation pathway and genes of Pseudomonas sp. strain TSN1. J Biosci Bioeng 126(3):355–362

    Article  CAS  Google Scholar 

  22. Sethi G, Shanmugam MK, Arfuso F, Kumar AP (2018) Role of RNF20 in cancer development and progression—a comprehensive review. Biosci Rep. https://doi.org/10.1042/BSR20171287

  23. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N (2020) Regulatory T cells and human disease. Annu Rev Immunol 38:541–566

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by research grants of the National Natural Science Foundation of China (81900914, 32090052), Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (2019B030301009) and Shenzhen science, technology and innovation committee (KQTD20170331145453160).

Author information

Author notes

  1. Xiangqian Luo, Lihua Mo and Xinxin Wang are contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Otolaryngology, Shenzhen Hospital, Southern Medial University, 1333 Xinhu Road, Shenzhen, 518055, China

    Xiangqian Luo, Lihua Mo & Dabo Liu

  2. Guangdong Provincial Regional Disease Key Laboratory, Room A7-509, 1066 Xueyuan Blvd, Shenzhen, 518055, China

    Xinxin Wang, Shuang Zhang, Huazhen Liu & Pingchang Yang

  3. Institute of Allergy, State Key Laboratory of Respiratory Diseases Allergy Division, Immunology of Shenzhen University, Shenzhen University, Room A7-509, 1066 Xueyuan Blvd, Shenzhen, 518055, China

    Xinxin Wang, Shuang Zhang, Huazhen Liu & Pingchang Yang

  4. Department of Respirology, Third Affiliated Hospital of Shenzhen University, Room A7-509, 1066 Xueyuan Blvd, Shenzhen, 518055, China

    Gaohui Wu & Qinmiao Huang

Authors
  1. Xiangqian Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lihua Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinxin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huazhen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gaohui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qinmiao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dabo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pingchang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XL, LM, XW, SZ, HL and GW performed experiments, analyzed data and reviewed the manuscript. PY, DL and QH organized the project and supervised experiments. PY designed the project and prepared the manuscript.

Corresponding authors

Correspondence to Qinmiao Huang, Dabo Liu or Pingchang Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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 3126 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

Luo, X., Mo, L., Wang, X. et al. Rnf20 inhibition enhances immunotherapy by improving regulatory T cell generation. Cell. Mol. Life Sci. 79, 588 (2022). https://doi.org/10.1007/s00018-022-04613-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04613-7

Keywords

Search

Navigation