Skip to main content

Advertisement

SpringerLink
Log in

High TOX expression on CD8+ T cells in pure red cell aplasia

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Thymocyte selection-associated high-mobility group box protein (TOX) is an important molecule regulating the development and exhaustion of T lymphocytes. Our aim is to investigate the role of TOX in the immune pathogenesis of pure red cell aplasia (PRCA). TOX expression of CD8+ lymphocytes from the peripheral blood of patients with PRCA was detected by flow cytometry. Additionally, the expression of immune checkpoint molecules PD1 and LAG3 and cytotoxic molecules perforin and granzyme B of CD8+ lymphocytes was measured. The quantity of CD4+CD25+CD127low T cells was analyzed. TOX expression on CD8+ T lymphocytes in PRCA patients was significantly increased (40.73 \(\pm\) 16.03 vs. 28.38 \(\pm\) 12.20). The expression levels of PD1 and LAG3 on CD8+ T lymphocytes in PCRA patients were significantly higher than those in the control group (34.18 \(\pm\) 13.26 vs. 21.76 \(\pm\) 9.22 and 14.17 \(\pm\) 13.74 vs. 7.24 \(\pm\) 5.44, respectively). The levels of perforin and granzyme in CD8+ T lymphocytes of PRCA patients were 48.60 \(\pm\) 19.02 and 46.66 \(\pm\) 25.49, respectively, which were significantly higher than those of the control group (31.46 \(\pm\) 7.82 and 16.17 \(\pm\) 4.84, respectively). The number of CD4+CD25+CD127low Treg cells in PRCA patients was significantly decreased (4.30 \(\pm\) 1.27 vs. 1.75 \(\pm\) 1.22). In PRCA patients, CD8+ T cells were activated and exhibited overexpression of TOX, PD1, LAG3, perforin, and granzyme B, while regulatory T cells decreased. These findings suggest that T cell abnormality plays a critical role in the pathogenesis of PRCA.

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

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Means RT (2016) Pure red cell aplasia. Blood 128(21):2504–2509

    Article  CAS  PubMed  Google Scholar 

  2. Gurnari C, Maciejewski JP (2021) How I manage acquired pure red cell aplasia in adults. Blood 137(15):2001–2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fisch P, Handgretinger R, Schaefer HE (2000) Pure red cell aplasia. Br J Haematol 111(4):1010–1022

    Article  CAS  PubMed  Google Scholar 

  4. Balasubramanian SK, Sadaps M, Thota S et al (2018) Rational management approach to pure red cell aplasia. Haematologica 103(2):221–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wilkinson B, Chen JY-F, Han P et al (2002) TOX: an HMG box protein implicated in the regulation of thymocyte selection. Nat Immunol 3(3):272–280

    Article  CAS  Google Scholar 

  6. Khan O, Giles JR, McDonald S et al (2019) TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571(7764):211–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scott AC, Dündar F, Zumbo P et al (2019) TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571(7764):270–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nitta H, Harada Y, Hyodo H, Kimura A, Harada H (2012) Expansion of CD8+/perforin+ T-cells predicts response to ciclosporin A therapy in patients with erythroid hypoplasia/aplasia. Br J Haematol 157(5):641–645

    Article  CAS  PubMed  Google Scholar 

  9. Nitta H, Mihara K, Sakai A, Kimura A (2010) Expansion of CD8+ /perforin+ effector memory T cells in the bone marrow of patients with thymoma-associated pure red cell aplasia. Br J Haematol 150(6):712–715

    Article  Google Scholar 

  10. Mori KL, Furukawa H, Hayashi K, Sugimoto K-JJ, Oshimi K (2003) Pure red cell aplasia associated with expansion of CD3+ CD8+ granular lymphocytes expressing cytotoxicity against HLA-E+ cells. Br J Haematol 123(1):147–153

    Article  PubMed  Google Scholar 

  11. Sekine T, Perez-Potti A, Nguyen S et al (2020) TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Sci Immunol 5(49):eaba7918

    Article  CAS  PubMed  Google Scholar 

  12. Maestre L, García-García JF, Jiménez S et al (2020) High-mobility group box (TOX) antibody a useful tool for the identification of B and T cell subpopulations. PLoS ONE 15(2):e0229743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alfei F, Kanev K, Hofmann M et al (2019) TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571(7764):265–269

    Article  CAS  PubMed  Google Scholar 

  14. Maurice NJ, Berner J, Taber AK, Zehn D, Prlic M (2021) Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells. JCI Insight 6(13):150744

    Article  PubMed  Google Scholar 

  15. Kumar BV, Connors TJ, Farber DL (2018) Human T cell development, localization, and function throughout life. Immunity 48(2):202–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nitta H, Mihara K, Sakai A, Kimura A (2010) Expansion of CD8+ /perforin+ effector memory T cells in the bone marrow of patients with thymoma-associated pure red cell aplasia. Br J Haematol 150(6):712–715

    Article  PubMed  Google Scholar 

  17. Hu X, Gu Y, Wang Y et al (2009) Increased CD4+ and CD8+ effector memory T cells in patients with aplastic anemia. Haematologica 94(3):428–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang Q, Bardhan K, Boussiotis VA, Patsoukis N (2021) The PD-1 Interactome. Adv Biol 5(9):e2100758

    Article  Google Scholar 

  19. Ruffo E, Wu RC, Bruno TC, Workman CJ, Vignali DAA (2019) Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin Immunol 42:101305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu H, Miao M, Zhang G et al (2009) Soluble PD-1 is associated with aberrant regulation of T cells activation in aplastic anemia. Immunol Invest 38(5):408–421

    Article  CAS  PubMed  Google Scholar 

  21. Zhao W, Zhang Y, Zhang P et al (2017) High programmed death 1 expression on T cells in aplastic anemia. Immunol Lett 183:44–51

    Article  CAS  PubMed  Google Scholar 

  22. Voskoboinik I, Whisstock JC, Trapani JA (2015) Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol 15(6):388–400

    Article  CAS  PubMed  Google Scholar 

  23. Josefowicz SZ, Lu L-F, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shi J, Ge M, Lu S et al (2012) Intrinsic impairment of CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia. Blood 120(8):1624–1632

    Article  CAS  PubMed  Google Scholar 

  25. Yan L, Fu R, Liu H et al (2015) Abnormal quantity and function of regulatory T cells in peripheral blood of patients with severe aplastic anemia. Cell Immunol 296(2):95–105

    Article  CAS  PubMed  Google Scholar 

  26. Dao ATT, Yamazaki H, Takamatsu H et al (2016) Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia. Ann Hematol 95(5):771–781

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from the Key Technology Research and Development Program of Tianjin China (18ZXDBSY00140), Tianjin Key Medical Discipline (Specialty) Construction Project.

Author information

Author notes

  1. Haiyue Niu, Li Yan, and Liping Yang contributed equally.

Authors and Affiliations

  1. Department of Hematology, General Hospital, Tianjin Medical University, Tianjin, 300052, China

    Haiyue Niu, Li Yan, Liping Yang, Mengying Zhang, Mengyuan Liu, Jie Ren, Zonghong Shao, Rong Fu, Limin Xing & Huaquan Wang

Authors
  1. Haiyue Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mengying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mengyuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zonghong Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rong Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Limin Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Huaquan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.W. and H.N. conceived and designed the study, collected, assembled, analyzed, and interpreted data, and wrote the manuscript; L.Y., L.Y., M.Z., M.L., J.R., Z.S., R.F., and L.X. contributed patients or analyzed and interpreted data; all authors read and approved the manuscript.

Corresponding author

Correspondence to Huaquan Wang.

Ethics declarations

Conflict of interest

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 1406 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

Niu, H., Yan, L., Yang, L. et al. High TOX expression on CD8+ T cells in pure red cell aplasia. Ann Hematol 102, 1247–1255 (2023). https://doi.org/10.1007/s00277-023-05174-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-023-05174-w

Keywords

Search

Navigation