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Inflammation Research

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Open Access 11-08-2022 | Multiple Sclerosis | Review

CD20⁺ T cells: an emerging T cell subset in human pathology

Author: Adrian Y. S. Lee

Published in: Inflammation Research | Issue 10-11/2022

Abstract

Introduction

Although CD20 is classically a B cell marker, in the last three decades, dim expression has been noted on a subset of T cells as well that has been independently verified by a number of groups. Our understanding of these cells and their function is not well established.

Methods

A thorough review of original articles on CD20⁺ T cells was undertaken of Pubmed by using combination of phrases including “CD20⁺”, “CD20-positive” and “T cells”. Articles in English were considered, and there was no time restriction.

Results

CD20⁺ T cells express the standard T cell markers and, in comparison to CD20¯ T cells, appear to express greater inflammatory cytokines and markers of effector function. Although the ontogeny of these cells is still being established, the current theory is that CD20 may be acquired by trogocytosis from B cells. CD20⁺ T cells may be found in healthy controls and in a wide range of pathologies including autoimmune diseases, haematological and non-haematological malignancies and human immunodeficiency virus (HIV) infections. One of the best studied diseases where these cells are found is multiple sclerosis (MS) where a number of therapeutic interventions, including anti-CD20 depletion, have been shown to effectively deplete these cells.

Conclusion

This review summarises the latest understanding of CD20⁺ T cells, their presence in various diseases, their putative function and how they may be an ongoing target of CD20-depleting agents. Unfortunately, our understanding of these cells is still at its infancy and ongoing study in a wider range of pathologies is required.

Pavlasova G, Mraz M. The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy. Haematologica. 2020;105(6):1494–506. https://doi.org/10.3324/haematol.2019.243543.CrossRefPubMedPubMedCentral

Li H, Ayer LM, Polyak MJ, Mutch CM, Petrie RJ, Gauthier L, et al. The CD20 calcium channel is localized to microvilli and constitutively associated with membrane rafts: antibody binding increases the affinity of the association through an epitope-dependent cross-linking-independent mechanism. J Biol Chem. 2004;279(19):19893–901. https://doi.org/10.1074/jbc.M400525200.CrossRefPubMed

van de Ven AA, Compeer EB, Bloem AC, van de Corput L, van Gijn M, van Montfrans JM, et al. Defective calcium signaling and disrupted CD20-B-cell receptor dissociation in patients with common variable immunodeficiency disorders. J Allergy Clin Immunol. 2012;129(3):755-61.e7. https://doi.org/10.1016/j.jaci.2011.10.020.CrossRefPubMed

Hultin LE, Hausner MA, Hultin PM, Giorgi JV. CD20 (pan-B cell) antigen is expressed at a low level on a subpopulation of human T lymphocytes. Cytometry. 1993;14(2):196–204. https://doi.org/10.1002/cyto.990140212.CrossRefPubMed

Vlaming M, Bilemjian V, Freile JÁ, Lourens HJ, van Rooij N, Huls G, et al. CD20 positive CD8 T cells are a unique and transcriptionally-distinct subset of T cells with distinct transmigration properties. Sci Rep. 2021;11(1):20499. https://doi.org/10.1038/s41598-021-00007-0.CrossRefPubMedPubMedCentral

de Bruyn M, Wiersma VR, Wouters MCA, Samplonius DF, Klip HG, Helfrich W, et al. CD20+ T cells have a predominantly Tc1 effector memory phenotype and are expanded in the ascites of patients with ovarian cancer. Oncoimmunology. 2015. https://doi.org/10.1080/2162402X.2014.999536.CrossRefPubMedPubMedCentral

Wilk E, Witte T, Marquardt N, Horvath T, Kalippke K, Scholz K, et al. Depletion of functionally active CD20+ T cells by rituximab treatment. Arthritis Rheum. 2009;60(12):3563–71. https://doi.org/10.1002/art.24998.CrossRefPubMed

Algino KM, Thomason RW, King DE, Montiel MM, Craig FE. CD20 (pan-B cell antigen) expression on bone marrow-derived T cells. Am J Clin Pathol. 1996;106(1):78–81. https://doi.org/10.1093/ajcp/106.1.78.CrossRefPubMed

Henry C, Ramadan A, Montcuquet N, Pallandre J-R, Mercier-Letondal P, Deschamps M, et al. CD3+CD20+ cells may be an artifact of flow cytometry: comment on the article by Wilk et al. Arthritis Rheum. 2010;62(8):2561–3. https://doi.org/10.1002/art.27527.CrossRefPubMed

10.

Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, et al. Features of human CD3+CD20+ T cells. J Immunol. 2016;197(4):1111–7. https://doi.org/10.4049/jimmunol.1600089.CrossRefPubMed

11.

Serra-Peinado C, Grau-Expósito J, Luque-Ballesteros L, Astorga-Gamaza A, Navarro J, Gallego-Rodriguez J, et al. Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab. Nat Commun. 2019;10(1):3705. https://doi.org/10.1038/s41467-019-11556-4.CrossRefPubMedPubMedCentral

12.

Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014;193(2):580–6. https://doi.org/10.4049/jimmunol.1400118.CrossRefPubMed

13.

Salva KA, Bennett D, Longley J, Guitart J, Wood GS. Multispectral imaging approach to the diagnosis of a CD20+ cutaneous T-cell lymphoproliferative disorder: a case report. Am J Dermatopathol. 2015;37(10):e116–21. https://doi.org/10.1097/dad.0000000000000323.CrossRefPubMedPubMedCentral

14.

Murayama Y, Mukai R, Sata T, Matsunaga S, Noguchi A, Yoshikawa Y. Transient expression of CD20 antigen (pan B cell marker) in activated lymph node T cells. Microbiol Immunol. 1996;40(6):467–71. https://doi.org/10.1111/j.1348-0421.1996.tb01096.x.CrossRefPubMed

15.

Ochs J, Nissimov N, Torke S, Freier M, Grondey K, Koch J, et al. Proinflammatory CD20(+) T cells contribute to CNS-directed autoimmunity. Sci Transl Med. 2022. https://doi.org/10.1126/scitranslmed.abi4632.CrossRefPubMed

16.

Eggleton P, Bremer E, Tarr JM, de Bruyn M, Helfrich W, Kendall A, et al. Frequency of Th17 CD20+ cells in the peripheral blood of rheumatoid arthritis patients is higher compared to healthy subjects. Arthritis Res Ther. 2011;13(6):R208. https://doi.org/10.1186/ar3541.CrossRefPubMedPubMedCentral

17.

Quendt C, Ochs J, Häusser-Kinzel S, Häusler D, Weber MS. Proinflammatory CD20(+) T cells are differentially affected by multiple sclerosis therapeutics. Ann Neurol. 2021;90(5):834–9. https://doi.org/10.1002/ana.26216.CrossRefPubMed

18.

Niu J, Zhai Z, Hao F, Zhang Y, Song Z, Zhong H. Dissection of a circulating CD3(+) CD20(+) T cell subpopulation in patients with psoriasis. Clin Exp Immunol. 2018;192(2):206–12. https://doi.org/10.1111/cei.13106.CrossRefPubMedPubMedCentral

19.

Hsiao C-C, Fransen NL, van den Bosch AMR, Brandwijk KIM, Huitinga I, Hamann J, et al. White matter lesions in multiple sclerosis are enriched for CD20dim CD8+ tissue-resident memory T cells. Eur J Immunol. 2021;51(2):483–6. https://doi.org/10.1002/eji.202048665.CrossRefPubMed

20.

von Essen MR, Ammitzbøll C, Hansen RH, Petersen ERS, McWilliam O, Marquart HV, et al. Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis. Brain. 2018;142(1):120–32. https://doi.org/10.1093/brain/awy301.CrossRef

21.

Boldrini VO, Quintiliano RPS, Silva LS, Damasceno A, Santos LMB, Farias AS. Cytotoxic profile of CD3+CD20+ T cells in progressive multiple sclerosis. Multiple sclerosis and related disorders. 2021;52: 103013. https://doi.org/10.1016/j.msard.2021.103013.CrossRefPubMed

22.

Holley JE, Bremer E, Kendall AC, de Bruyn M, Helfrich W, Tarr JM, et al. CD20+inflammatory T-cells are present in blood and brain of multiple sclerosis patients and can be selectively targeted for apoptotic elimination. Mult Scler Relat Disord. 2014;3(5):650–8. https://doi.org/10.1016/j.msard.2014.06.001.CrossRefPubMed

23.

Sabatino JJ Jr, Wilson MR, Calabresi PA, Hauser SL, Schneck JP, Zamvil SS. Anti-CD20 therapy depletes activated myelin-specific CD8(+) T cells in multiple sclerosis. Proc Natl Acad Sci U S A. 2019;116(51):25800–7. https://doi.org/10.1073/pnas.1915309116.CrossRefPubMedPubMedCentral

24.

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209–20. https://doi.org/10.1056/NEJMoa1606468.CrossRefPubMed

25.

Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006;180(1–2):63–70. https://doi.org/10.1016/j.jneuroim.2006.06.029.CrossRefPubMedPubMedCentral

26.

Capasso N, Nozzolillo A, Scalia G, Lanzillo R, Carotenuto A, De Angelis M, et al. Ocrelizumab depletes T-lymphocytes more than rituximab in multiple sclerosis. Mult Scler Relat Disord. 2021;49: 102802. https://doi.org/10.1016/j.msard.2021.102802.CrossRefPubMed

27.

Gingele S, Jacobus TL, Konen FF, Hümmert MW, Sühs KW, Schwenkenbecher P, et al. Ocrelizumab depletes CD20⁺ T cells in multiple sclerosis patients. Cells. 2018. https://doi.org/10.3390/cells8010012.CrossRefPubMedPubMedCentral

28.

Howlett-Prieto Q, Feng X, Kramer JF, Kramer KJ, Houston TW, Reder AT. Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis. Mult Scler J. 2021;27(14):2170–9. https://doi.org/10.1177/13524585211003301.CrossRef

29.

Giannini D, Antonucci M, Petrelli F, Bilia S, Alunno A, Puxeddu I. One year in review 2020: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2020;38(3):387–97.PubMed

30.

Bergantini L, d’Alessandro M, Cameli P, Vietri L, Vagaggini C, Perrone A, et al. Effects of rituximab therapy on B cell differentiation and depletion. Clin Rheumatol. 2020;39(5):1415–21. https://doi.org/10.1007/s10067-020-04996-7.CrossRefPubMed

31.

van de Veerdonk FL, Lauwerys B, Marijnissen RJ, Timmermans K, Di Padova F, Koenders MI, et al. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum. 2011;63(6):1507–16. https://doi.org/10.1002/art.30314.CrossRefPubMed

32.

Chen M, Zhang Q, Wei Y, Wan Q, Xu M, Chen X. Anti-CD20 therapy ameliorates β cell function and rebalances Th17/Treg cells in NOD mice. Endocrine. 2022. https://doi.org/10.1007/s12020-021-02965-x.CrossRefPubMedPubMedCentral

33.

Nussbaum L, Chen YL, Ogg GS. Role of regulatory T cells in psoriasis pathogenesis and treatment. Br J Dermatol. 2021;184(1):14–24. https://doi.org/10.1111/bjd.19380.CrossRefPubMed

34.

Fragiotta S, Mangino G, Iuliano M, Potenza C, Bernardini N, Skroza N, et al. Role of CD 20(+) T cells and related cytokines in mediating retinal microvascular changes and ocular complications in chronic-plaque type psoriasis. Cytokine. 2020;136: 155253. https://doi.org/10.1016/j.cyto.2020.155253.CrossRefPubMed

35.

Sato T, Ohno S, Hayashi T, Sato C, Kohu K, Satake M, et al. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity. 2005;22(3):317–28. https://doi.org/10.1016/j.immuni.2005.01.012.CrossRefPubMed

36.

Alunno A, Carubbi F, Bistoni O, Caterbi S, Bartoloni E, Di Benedetto P, et al. Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren’s syndrome: a pilot study. Clin Exp Immunol. 2016;184(3):284–92. https://doi.org/10.1111/cei.12771.CrossRefPubMedPubMedCentral

37.

Hwang SH, Woo JS, Moon J, Yang S, Park JS, Lee J, et al. IL-17 and CCR9(+)α4β7(-) Th17 cells promote salivary gland inflammation, dysfunction, and cell death in Sjögren’s syndrome. Front Immunol. 2021;12: 721453. https://doi.org/10.3389/fimmu.2021.721453.CrossRefPubMedPubMedCentral

38.

Li YL, Wang HP, Zhang C, Zhai ZM. CD20-positive primary nasal peripheral T-cell lymphoma: an analysis of one case and review of the literature. Cytometry B Clin Cytom. 2020;98(4):348–54. https://doi.org/10.1002/cyto.b.21852.CrossRefPubMed

39.

Gadgeel M, Al-Qanber B, Buck S, Savaşan S. CD20+ T cells in primary mediastinal large b cell lymphoma microenvironment. Cytometry B Clin Cytom. 2020;98(1):16–8. https://doi.org/10.1002/cyto.b.21832.CrossRefPubMed

40.

Lockhart G, Kaushal M, Azimi A, Nana-sinkam P. Extranodal marginal zone lymphoma of the pleura presenting as unilateral pleural effusion: a case report. Chest. 2014;146(4):657A. https://doi.org/10.1378/chest.1991967.CrossRef

41.

Sun T, Akalin A, Rodacker M, Braun T. CD20 positive T cell lymphoma: is it a real entity? J Clin Pathol. 2004;57(4):442–4. https://doi.org/10.1136/jcp.2003.011734.CrossRefPubMedPubMedCentral

42.

Quintanilla-Martinez L, Preffer F, Rubin D, Ferry JA, Harris NL. CD20+ T-cell lymphoma. Neoplastic transformation of a normal T-cell subset. Am J Clin Pathol. 1994;102(4):483–9. https://doi.org/10.1093/ajcp/102.4.483.CrossRefPubMed

43.

Martin B, Stefanato C, Whittaker S, Robson A. Primary cutaneous CD20-positive T-cell lymphoma. J Cutan Pathol. 2011;38(8):663–9. https://doi.org/10.1111/j.1600-0560.2011.01709.x.CrossRefPubMed

44.

Wang X, Ng CS, Chen C, Yu G, Yin W. An unusual case report of indolent T-cell lymphoproliferative disorder with aberrant CD20 expression involving the gastrointestinal tract and bone marrow. Diagn Pathol. 2018;13(1):82. https://doi.org/10.1186/s13000-018-0762-4.CrossRefPubMedPubMedCentral

45.

Gonin J, Kadiri H, Bensaci S, Le Tourneau A, Molina TJ, Diebold J, et al. Primary mediastinal anaplastic alk-1-positive large-cell lymphoma of T/NK-cell type expressing CD20. Virchows Arch. 2007;450(3):355–8. https://doi.org/10.1007/s00428-007-0371-1.CrossRefPubMed

46.

Sukumaran R, Nair RA. Adult T cell leukemia/lymphoma complicated by proliferation of large B cells: a diagnostic dilemma. J Hematop. 2018;11(3):83–6. https://doi.org/10.1007/s12308-018-0326-2.CrossRef

47.

Kakinoki Y, Hashiguchi J, Ishio T, Chiba K, Niino D, Ohshima K. CD20-positive primary gastric T-cell lymphoma poorly responding to initial treatment with rituximab plus CHOP, and a literature review. Int J Hematol. 2015;102(6):702–8. https://doi.org/10.1007/s12185-015-1841-x.CrossRefPubMed

48.

Miyazaki K, Ohsaka M, Suzuki Y, Danbara M, Horie R, Higashihara M. CD20-positive T-cell large granular lymphocyte leukemia: case report and review of the literature. Intern Med. 2009;48(16):1443–7. https://doi.org/10.2169/internalmedicine.48.2141.CrossRefPubMed

49.

Warzynski MJ, Graham DM, Axtell RA, Zakem MH, Rotman RK. Low level CD20 expression on T cell malignancies. Cytometry. 1994;18(2):88–92. https://doi.org/10.1002/cyto.990180206.CrossRefPubMed

50.

Kawano R, Niino D, Ohshima K. Six cases of CD20-positive adult T-cell leukemia. J Clin Exp Hematop. 2016;56(2):119–25. https://doi.org/10.3960/jslrt.56.119.CrossRefPubMedPubMedCentral

51.

Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol. 2010;185(9):4977–82. https://doi.org/10.4049/jimmunol.1001323.CrossRefPubMed

52.

van der Leun AM, Thommen DS, Schumacher TN. CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020;20(4):218–32. https://doi.org/10.1038/s41568-019-0235-4.CrossRefPubMedPubMedCentral

53.

Mudd TW Jr, Lu C, Klement JD, Liu K. MS4A1 expression and function in T cells in the colorectal cancer tumor microenvironment. Cell Immunol. 2021;360: 104260. https://doi.org/10.1016/j.cellimm.2020.104260.CrossRefPubMed

54.

Förster F, Singla A, Arora SK, Schmidt RE, Jacobs R. CD20+ T cell numbers are decreased in untreated HIV-1 patients and recover after HAART. Immunol Lett. 2012;146(1–2):74–8. https://doi.org/10.1016/j.imlet.2012.05.004.CrossRefPubMed

55.

Martin GE, Pace M, Thornhill JP, Phetsouphanh C, Meyerowitz J, Gossez M, et al. CD32-expressing CD4 T cells are phenotypically diverse and can contain proviral HIV DNA. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.00928.CrossRefPubMedPubMedCentral

56.

Huot N, Rascle P, Planchais C, Contreras V, Passaes C, Le Grand R, et al. CD32+CD4+ T cells sharing B cell properties increase with simian immunodeficiency virus replication in lymphoid tissues. Front Immunol. 2021;12: 695148. https://doi.org/10.3389/fimmu.2021.695148.CrossRefPubMedPubMedCentral

57.

Shen C-F, Wang S-M, Ho T-S, Liu C-C. Clinical features of community acquired adenovirus pneumonia during the 2011 community outbreak in Southern Taiwan: role of host immune response. BMC Infect Dis. 2017;17(1):196. https://doi.org/10.1186/s12879-017-2272-5.CrossRefPubMedPubMedCentral

58.

Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol. 2019;41(3):283–97. https://doi.org/10.1007/s00281-019-00733-8.CrossRefPubMed

Title: CD20+ T cells: an emerging T cell subset in human pathology
Author: Adrian Y. S. Lee
Publication date: 11-08-2022
Publisher: Springer International Publishing
Keywords: Multiple Sclerosis
Human Immunodeficiency Virus
Pathology
Published in: Inflammation Research / Issue 10-11/2022
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-022-01622-x

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