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Altered levels of circulating CD8+CXCR5+PD-1+T follicular cytotoxic cells in primary Sjögren’s syndrome

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Abstract

Background

Circulating CD8+ T-cells expressing the C-X-C chemokine receptor type 5 (CXCR5) (CD8+CXCR5+T), a recently identified follicular cytotoxic T cell subset, are involved in antiviral immunity and autoimmunity, but their abundance and role in the pathogenesis of primary Sjögren syndrome (pSS) are unknown.

Methods

Circulating CD8+CXCR5+T cell and CD8+ regulatory T cells (CD8+Treg) were evaluated in 49 pSS patients (19 patients with pulmonary involvement) and 24 age- and sex-matched healthy controls (HCs) by flow cytometry. Orthogonal partial least squares discriminant analysis (OPLS-DA) was performed, and receiver operating characteristic curves (ROC) were generated to identify characteristic cell subsets. Spearman’s correlation analysis was conducted to examine the relationships between CD8+ T cell subsets and clinical features.

Results

The proportions and numbers of CD8+CXCR5+, CD8 + CXCR5+ programmed death 1-positive (PD-1+), and CD8+CXCR5−PD-1+T cells were significantly higher, whereas those of CD8+Treg were markedly lower, in pSS patients than HCs. The CD8+CXCR5+PD-1+T cell to CD8+Treg ratio had the greatest discriminatory power for pSS and HCs according to OPLS-DA and ROC analyses. The increased numbers of CD8+CXCR5+T cells and CD8+CXCR5+PD-1+T cells were strongly associated with those of CD4+CXCR5+T and B cells. The proportions and numbers of CD8+CXCR5+PD-1+T cells were increased in pSS patients with lung involvement.

Conclusions

We identified a new CD8+CXCR5+PD-1+T subset, which was increased in abundance in pSS patients, particularly those with lung involvement, compared with HCs. Also, the CD8+CXCR5+PD-1+T to CD8+Treg ratio may be useful for identifying pSS. Our findings suggest that targeting follicular CD8+T cell subsets has therapeutic potential for pSS.

Key Points

• CD8+CXCR5+ T cells were expanded in the circulation of patients with pSS.

• Reduced numbers CD8+Treg cells in pSS patients.

• Increased CD8+CXCR5+PD-1+T cells in pSS patients with pulmonary involvement.

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References

  1. Fox RI (2005) Sjogren’s syndrome. Lancet 366:321–331. https://doi.org/10.1016/S0140-6736(05)66990-5

    Article  CAS  PubMed  Google Scholar 

  2. Astorri E, Scrivo R, Bombardieri M, Picarelli G, Pecorella I, Porzia A et al (2014) CX3CL1 and CX3CR1 expression in tertiary lymphoid structures in salivary gland infiltrates: fractalkine contribution to lymphoid neogenesis in Sjogren’s syndrome. Rheumatology (Oxford) 53:611–620. https://doi.org/10.1093/rheumatology/ket401

    Article  CAS  Google Scholar 

  3. Fonseca VR, Romão VC, Agua DA, Santos M, Presa DL, Ferreira AC et al (2018) The ratio of blood T follicular regulatory cells to T follicular helper cells marks ectopic lymphoid structure formation while activated follicular helper T cells indicate disease activity in primary Sjogren’s syndrome. Arthritis Rheumatol 70:774–784. https://doi.org/10.1002/art.40424

    Article  CAS  PubMed  Google Scholar 

  4. Ueno H (2016) T follicular helper cells in human autoimmunity. Curr Opin Immunol 43:24–31. https://doi.org/10.1016/j.coi.2016.08.003

    Article  CAS  PubMed  Google Scholar 

  5. Federico PC, Natalia AT, Maria TR (2018) Circulating CXCR5-expressing CD8+ T-cells are major producers of IL-21 and associate with limited HIV replication. J Acquir Immune Defic Syndr 78:473–482. https://doi.org/10.1097/QAI.0000000000001700

    Article  CAS  Google Scholar 

  6. Bai M, Zheng Y, Liu H, Su BW, Zhan Y, He H (2017) CXCR5+ CD8+ T cells potently infiltrate pancreatic tumors and present high functionality. Exp Cell Res 361:39–45. https://doi.org/10.1016/j.yexcr.2017.09.039

    Article  CAS  PubMed  Google Scholar 

  7. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC et al (2016) Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537:417–421. https://doi.org/10.1038/nature19330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kang YM, Zhang XY, Wagner UG, Yang HY, Beckenbaugh RD, Kurtin PJ et al (2002) CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 195:1325–1336. https://doi.org/10.1084/jem.20011565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shan Q, Zeng ZH, Xing SJ, Li FY, Hartwig SM, Gullicksrud JA et al (2017) The transcription factor Runx3 guards cytotoxic CD8(+) effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol 18:931–939. https://doi.org/10.1038/ni.3773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen Y, Yu M, Zheng Y, Fu GP, Xin G, Zhu W et al (2019) CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance. Nat Commun 10:4415. https://doi.org/10.1038/s41467-019-12446-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Le KS, Patricia AT, Tarte K, Rey FG, Granjeaud S, Orlanducci F et al (2018) CXCR5 and ICOS expression identifies a CD8 T-cell subset with T features in Hodgkin lymphomas. Blood Adv 2:1889–1900. https://doi.org/10.1182/bloodadvances

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 33:775–787. https://doi.org/10.1016/j.cell.2008.05.009

    Article  CAS  Google Scholar 

  13. Tang XL, Smith TR, Kumar V (2005) Specific control of immunity by regulatory CD8 T cells. Cell Mol Immunol 2:11–19

    CAS  PubMed  Google Scholar 

  14. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic selftolerance and negative control of immune responses. Annu Rev Immunol 22:531–562. https://doi.org/10.1146/annurev.immunol.21.120601.141122

    Article  CAS  PubMed  Google Scholar 

  15. Dinesh RK, Skaggs BJ, La CA, Hahn BH, Singh RP (2010) CD8+ Tregs in lupus, autoimmunity, and beyond. Autoimmun Rev 9:560–568. https://doi.org/10.1016/j.autrev.2010.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sinha S, Itani FR, Karandikar NJ (2014) Immune regulation of multiple sclerosis by CD8+ T cells. Immunol Res 59:254–265. https://doi.org/10.1007/s12026-014-8529-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tulunay A, Yavuz S, Direskeneli H, Eksioglu-Demiralp E (2008) CD8+CD28-, suppressive T cells in systemic lupus erythematosus. Lupus 17:630–637. https://doi.org/10.1177/0961203308089400

    Article  CAS  PubMed  Google Scholar 

  18. Brimnes J, Allez M, Dotan I, Shao L, Nakazawa A, Mayer L (2005) Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease. J Immunol 174:5814–5822. https://doi.org/10.4049/jimmunol.174.9.5814

    Article  CAS  PubMed  Google Scholar 

  19. Correale J, Villa A (2010) Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis. Ann Neurol 67:625–638. https://doi.org/10.1002/ana.21944

    Article  CAS  PubMed  Google Scholar 

  20. Kim HJ, Verbinne B, Tang X, Lu L, Cantor H (2010) Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467:328–332. https://doi.org/10.1038/nature09370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE et al (2002) European Study Group on Classification Criteria for Sjögren’s Syndrome. Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558. https://doi.org/10.1136/ard.61.6.554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E et al (2010) EULAR Sjogren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis 69:1103–1109. https://doi.org/10.1136/ard.2009.110619

    Article  PubMed  Google Scholar 

  23. Chisholm DM, Mason DK (1968) Labial salivary gland biopsy in Sjögren’s disease. J Clin Pathol 21:656–660. https://doi.org/10.1136/jcp.21.5.656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Carsons SE, Vivino FB, Parke A, Carteron N, Sankar V, Brasington R et al (2017) Treatment guidelines for rheumatologic manifestations of Sjögren’s Syndrome: use of biologic agents, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken) 69:517–527. https://doi.org/10.1002/acr.22968

    Article  Google Scholar 

  25. Yazisiz V, Arslan G, Ozbudak IH, Turker S, Erbasan F, Avci AB et al (2010) Lung involvement in patients with primary Sjogren’s syndrome: what are the predictors? Rheumatol Int 30:1317–1324. https://doi.org/10.1007/s00296-009-1152-8

    Article  PubMed  Google Scholar 

  26. Li BC, Guo QL, Wang YY, Su R, Gao C, Zhao JF et al (2020) Increased serum interleukin-2 levels are associated with abnormal peripheral blood natural killer cell levels in patients with active rheumatoid arthriti. Mediators Inflamm 2020:6108342. https://doi.org/10.1155/2020/6108342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kampolis CF, Fragkioudaki S, Mavragani CP, Zormpala A, Samakovli A, Moutsopoulos HM (2018) Prevalence and spectrum of symptomatic pulmonary involvement in primary Sjögren’s syndrome. Clin Exp Rheumatol 112:94–101

    Google Scholar 

  28. Flament T, Bigot A, Chaigne B, Henique H, Diot E, Marchand-Adam S (2016) Pulmonary manifestations of Sjögren’s syndrome. Eur Respir Rev 25:110–123. https://doi.org/10.1183/16000617.0011-2016

    Article  PubMed  Google Scholar 

  29. Leong YA, Chen YP, Ong HS, Wu D, Man K, Deleage C et al (2016) CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles. Nat Immunol 17:1187–1196. https://doi.org/10.1038/ni.3543

    Article  CAS  PubMed  Google Scholar 

  30. Ferrando-Martinez S, Moysi E, Pegu A, Andrews S, Makamdop KN, Ambrozak D et al (2018) Accumulation of follicular CD8+ T cells in pathogenic SIV infection. J Clin Inves 128:2089–2103. https://doi.org/10.1172/JCI96207

    Article  Google Scholar 

  31. Nurieva RI, Podd A, Chen YH, Alekseev AM, Yu M, Qi XP et al (2012) STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem 287:11234–11239. https://doi.org/10.1074/jbc.M111.324046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou Y, Guo LQ, Sun HW, Xu JB, Ba T (2018) CXCR5+ CD8 T cells displayed higher activation potential despite high PD-1 expression, in tumor-involved lymph nodes from patients with thyroid cancer. Int Immunopharmacol 62:114–119. https://doi.org/10.1016/j.intimp.2018.07.002

    Article  CAS  PubMed  Google Scholar 

  33. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C (2008) A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29:127–137. https://doi.org/10.1016/j.immuni.2008.06.001

    Article  CAS  PubMed  Google Scholar 

  34. Malik A, Sharma D, Zhu QF, Karki R, Guy CS, Vogel P et al (2016) IL-33 regulates the IgA-microbiota axis to restrain IL-1alpha-dependent colitis and tumorigenesis. J Clin Invest 126:4469–4481. https://doi.org/10.1172/JCI88625

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lin J, Yu Y, Ma JL, Ren CY, Chen WQ (2019) PD-1+CXCR5-CD4+T cells are correlated with the severity of systemic lupus erythematosus. Rheumatology (Oxford) 58:2188–2192. https://doi.org/10.1093/rheumatology/kez228

    Article  CAS  Google Scholar 

  36. Churlaud G, Pitoiset F, Jebbawi F, Lorenzon R, Bellier B, Rosenzwajg M et al (2015) Human and mouse CD8(+)CD25(+)FOXP3(+) regulatory T cells at steady state and during interleukin-2 therapy. Front Immunol 6:171. https://doi.org/10.3389/fimmu.2015.00171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Miao M, Hao ZY, Guo YY, Zhang XY, Zhang SX, Luo J et al (2018) Short-term and low-dose IL-2 therapy restores the Th17/Treg balance in the peripheral blood of patients with primary Sjögren’s syndrome. Ann Rheum Dis 77:1838–1840. https://doi.org/10.1136/annrheumdis-2018-213036

    Article  CAS  PubMed  Google Scholar 

  38. Eusebio M, Kraszula L, Kupczyk M, Kuna P, Pietruczuk M (2012) Low frequency of CD8+CD25+FOXP3(BRIGHT) T cells and FOXP3 mRNA expression in the peripheral blood of allergic asthma patients. J Biol Regul Homeost Agents 26:211–220

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by the Nature Fund Projects of Shanxi Science and Technology Department (201901D111377), the Scientific Research Project of Health commission of Shanxi Province (2019044), the Research Project Supported by Shanxi Scholarship Council of China (2020–191), and Science and Technology Innovation Project of Shanxi Province (2020SYS08).

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Author notes

  1. Xuwen Zhai, Yanlin Wang and Hui Guo are contributed equally to this work.

Authors and Affiliations

  1. The Clinical Skills Teaching, Simulation Hospital of Shanxi Medical University, Jinzhong, 030600, Shanxi, China

    Xuwen Zhai

  2. Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Yanlin Wang, Zhaojun Liang, Min Feng, Yanyao Wu, Yan Qin, Xiangcong Zhao & Jing Luo

  3. Division of Nephrology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Hui Guo

  4. Division of Nephrology, Department of Medicine, Shenzhen Baoan Shiyan People’s Hospital, Shenzhen, 518005, Guangdong, China

    Hui Guo

  5. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Chong Gao

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  1. Xuwen Zhai
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Zhai, X., Wang, Y., Guo, H. et al. Altered levels of circulating CD8+CXCR5+PD-1+T follicular cytotoxic cells in primary Sjögren’s syndrome. Clin Rheumatol 41, 1697–1708 (2022). https://doi.org/10.1007/s10067-022-06098-y

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