Identification of a Super-functional Tfh-like Subpopulation in Murine Lupus by Pattern Perception

Overview

Journal Elife

Specialty Biology

Date 2020 May 23

PMID 32441253

Citations 5

Authors

Stefanie Gryzik

Yen Hoang

Timo Lischke

Elodie Mohr

Melanie Venzke

Isabelle Kadner

Josephine Poetzsch

Detlef Groth

Andreas Radbruch

Andreas Hutloff

Ria Baumgrass

Affiliations

Soon will be listed here.

Abstract

Dysregulated cytokine expression by T cells plays a pivotal role in the pathogenesis of autoimmune diseases. However, the identification of the corresponding pathogenic subpopulations is a challenge, since a distinction between physiological variation and a new quality in the expression of protein markers requires combinatorial evaluation. Here, we were able to identify a super-functional follicular helper T cell (Tfh)-like subpopulation in lupus-prone NZBxW mice with our binning approach "pattern recognition of immune cells (PRI)". PRI uncovered a subpopulation of IL-21 IFN-γ PD-1 CD40L CXCR5 Bcl-6 T cells specifically expanded in diseased mice. In addition, these cells express high levels of TNF-α and IL-2, and provide B cell help for IgG production in an IL-21 and CD40L dependent manner. This super-functional T cell subset might be a superior driver of autoimmune processes due to a polyfunctional and high cytokine expression combined with Tfh-like properties.

Citing Articles

Identification of a New and Effective Marker Combination for a Standardized and Automated Bin-Based Basophil Activation Test (BAT) Analysis.

Groffmann J, Hoppe I, Ahmed W, Hoang Y, Gryzik S, Radbruch A Diagnostics (Basel). 2024; 14(17).

PMID: 39272743 PMC: 11394212. DOI: 10.3390/diagnostics14171959.

The differentiation courses of the Tfh cells: a new perspective on autoimmune disease pathogenesis and treatment.

Yang Q, Zhang F, Chen H, Hu Y, Yang N, Yang W Biosci Rep. 2023; 44(1).

PMID: 38051200 PMC: 10830446. DOI: 10.1042/BSR20231723.

PRI: Re-Analysis of a Public Mass Cytometry Dataset Reveals Patterns of Effective Tumor Treatments.

Hoang Y, Gryzik S, Hoppe I, Rybak A, Schadlich M, Kadner I Front Immunol. 2022; 13:849329.

PMID: 35592315 PMC: 9110672. DOI: 10.3389/fimmu.2022.849329.

[How T lymphocytes coordinate rheumatic inflammation].

Chang H, Radbruch A, Kallinich T, Mashreghi M, Hegazy A, Kruglov A Z Rheumatol. 2022; 81(8):635-641.

PMID: 35380250 DOI: 10.1007/s00393-022-01186-5.

Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases.

Risso V, Lafont E, Le Gallo M Cell Death Dis. 2022; 13(3):248.

PMID: 35301281 PMC: 8931059. DOI: 10.1038/s41419-022-04688-x.

References

Ekman I, Ihantola E, Viisanen T, Rao D, Nanto-Salonen K, Knip M . Circulating CXCR5PD-1 peripheral T helper cells are associated with progression to type 1 diabetes. Diabetologia. 2019; 62(9):1681-1688. PMC: 6677711. DOI: 10.1007/s00125-019-4936-8. View

von Spee-Mayer C, Siegert E, Abdirama D, Rose A, Klaus A, Alexander T . Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2015; 75(7):1407-15. DOI: 10.1136/annrheumdis-2015-207776. View

Spitzer M, Gherardini P, Fragiadakis G, Bhattacharya N, Yuan R, Hotson A . IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science. 2015; 349(6244):1259425. PMC: 4537647. DOI: 10.1126/science.1259425. View

Wang L, Zhao P, Ma L, Shan Y, Jiang Z, Wang J . Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus. J Rheumatol. 2014; 41(9):1781-92. DOI: 10.3899/jrheum.131025. View

Levine J, Simonds E, Bendall S, Davis K, Amir E, Tadmor M . Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis. Cell. 2015; 162(1):184-97. PMC: 4508757. DOI: 10.1016/j.cell.2015.05.047. View

Westerhof L, McGuire K, MacLellan L, Flynn A, Gray J, Thomas M . Multifunctional cytokine production reveals functional superiority of memory CD4 T cells. Eur J Immunol. 2019; 49(11):2019-2029. PMC: 6900100. DOI: 10.1002/eji.201848026. View

Tilstra J, Avery L, Menk A, Gordon R, Smita S, Kane L . Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J Clin Invest. 2018; 128(11):4884-4897. PMC: 6205402. DOI: 10.1172/JCI120859. View

Facciotti F, Gagliani N, Haringer B, Alfen J, Penatti A, Maglie S . IL-10-producing forkhead box protein 3-negative regulatory T cells inhibit B-cell responses and are involved in systemic lupus erythematosus. J Allergy Clin Immunol. 2015; 137(1):318-321.e5. DOI: 10.1016/j.jaci.2015.06.044. View

Liu S, King C . IL-21-producing Th cells in immunity and autoimmunity. J Immunol. 2013; 191(7):3501-6. DOI: 10.4049/jimmunol.1301454. View

10.

Haynes N, Allen C, Lesley R, Ansel K, Killeen N, Cyster J . Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J Immunol. 2007; 179(8):5099-108. DOI: 10.4049/jimmunol.179.8.5099. View

11.

Larsen M, Sauce D, Arnaud L, Fastenackels S, Appay V, Gorochov G . Evaluating cellular polyfunctionality with a novel polyfunctionality index. PLoS One. 2012; 7(7):e42403. PMC: 3408490. DOI: 10.1371/journal.pone.0042403. View

12.

Kannanganat S, Ibegbu C, Chennareddi L, Robinson H, Amara R . Multiple-cytokine-producing antiviral CD4 T cells are functionally superior to single-cytokine-producing cells. J Virol. 2007; 81(16):8468-76. PMC: 1951378. DOI: 10.1128/JVI.00228-07. View

13.

Cheng Q, Mumtaz I, Khodadadi L, Radbruch A, Hoyer B, Hiepe F . Autoantibodies from long-lived 'memory' plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis. 2013; 72(12):2011-7. DOI: 10.1136/annrheumdis-2013-203455. View

14.

Peng S, Szabo S, Glimcher L . T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci U S A. 2002; 99(8):5545-50. PMC: 122806. DOI: 10.1073/pnas.082114899. View

15.

Jiao Q, Liu C, Yang Z, Ding Q, Wang M, Li M . Upregulated PD-1 Expression Is Associated with the Development of Systemic Lupus Erythematosus, but Not the PD-1.1 Allele of the PDCD1 Gene. Int J Genomics. 2014; 2014:950903. PMC: 4016872. DOI: 10.1155/2014/950903. View

16.

Swain S . Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity. 1994; 1(7):543-52. DOI: 10.1016/1074-7613(94)90044-2. View

17.

Fang D, Cui K, Mao K, Hu G, Li R, Zheng M . Transient T-bet expression functionally specifies a distinct T follicular helper subset. J Exp Med. 2018; 215(11):2705-2714. PMC: 6219743. DOI: 10.1084/jem.20180927. View

18.

Choi J, Seth A, Kashgarian M, Terrillon S, Fung E, Huang L . Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus. J Immunol. 2017; 198(7):2578-2588. PMC: 5360548. DOI: 10.4049/jimmunol.1601687. View

19.

Luthje K, Kallies A, Shimohakamada Y, Belz G, Light A, Tarlinton D . The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat Immunol. 2012; 13(5):491-8. DOI: 10.1038/ni.2261. View

20.

Hayashi Y, Utsuyama M, Kurashima C, Hirokawa K . Spontaneous development of organ-specific autoimmune lesions in aged C57BL/6 mice. Clin Exp Immunol. 1989; 78(1):120-6. PMC: 1534591. View