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T Cell Abnormalities in the Pathogenesis of Systemic Lupus Erythematosus: an Update

  • Systemic Lupus Erythematosus (G Tsokos, Section Editor)
  • Published:
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Abstract

Purpose of Review

Systemic lupus erythematosus is a complex disease with broad spectrum of clinical manifestations. In addition to abnormal B cell responsive leading to autoantibody production, various T cells also play different roles in promoting systemic autoimmunity and end organ damage. We aim to provide a review on recent developments in how abnormalities in different T cells subsets contribute to systemic lupus erythematosus pathogenesis and how they inform the consideration of new promising therapeutics.

Recent Findings

Distinct subsets of T cells known as T follicular helper cells enable the production of pathogenic autoantibodies. Detailed understanding of the B cell helping T cell subsets should improve the performance of clinical trials targeting the cognate T:B cell interaction. CD8+ T cells play a role in peripheral tolerance and reversal of its exhausted phenotype could potentially alleviate both systemic autoimmunity and the risk of infection. Research on the abnormal lupus T cell signaling also leads to putative therapeutic targets able to restore interleukin-2 production and suppress the production of the pathogenic IL-17 cytokine. Recently, several studies have focused on dissecting T cell populations located in the damaged organs, aiming to target the pathogenic processes specific to each organ.

Summary

Numerous T cell subsets play distinct roles in SLE pathogenesis and recent research in understanding abnormal signaling pathways, cellular metabolism, and environmental cues pave the way for the development of novel therapeutics.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Olsen NJ, Karp DR. Autoantibodies and SLE: the threshold for disease. Nat Rev Rheumatol. 2014;10(3):181–6. https://doi.org/10.1038/nrrheum.2013.184.

    Article  PubMed  Google Scholar 

  2. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110–21. https://doi.org/10.1056/NEJMra1100359.

    Article  CAS  PubMed  Google Scholar 

  3. Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol. 2020;21(6):605–14. https://doi.org/10.1038/s41590-020-0677-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Seth A, Craft J. Spatial and functional heterogeneity of follicular helper T cells in autoimmunity. Curr Opin Immunol. 2019;61:1–9. https://doi.org/10.1016/j.coi.2019.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Apostolidis SA, Lieberman LA, Kis-Toth K, Crispín JC, Tsokos GC. The dysregulation of cytokine networks in systemic lupus erythematosus. J Interf Cytokine Res. 2011;31(10):769–79. https://doi.org/10.1089/jir.2011.0029.

    Article  CAS  Google Scholar 

  6. Wellmann U, Letz M, Herrmann M, Angermüller S, Kalden JR, Winkler TH. The evolution of human anti-double-stranded DNA autoantibodies. Proc Natl Acad Sci U S A. 2005;102(26):9258–63. https://doi.org/10.1073/pnas.0500132102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guo W, Smith D, Aviszus K, Detanico T, Heiser RA, Wysocki LJ. Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity. J Exp Med. 2010;207(10):2225–37. https://doi.org/10.1084/jem.20092712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sobel ES, Kakkanaiah VN, Kakkanaiah M, Cheek RL, Cohen PL, Eisenberg RA. T-B collaboration for autoantibody production in lpr mice is cognate and MHC-restricted. J Immunol. 1994;152(12):6011–6.

    CAS  PubMed  Google Scholar 

  9. Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010;207(2):365–78. https://doi.org/10.1084/jem.20091777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal Centre formation. Nature. 2008;455(7214):764–9. https://doi.org/10.1038/nature07345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Randall TD, Heath AW, Santos-Argumedo L, Howard MC, Weissman IL, Lund FE. Arrest of B lymphocyte terminal differentiation by CD40 signaling: mechanism for lack of antibody-secreting cells in germinal centers. Immunity. 1998;8(6):733–42. https://doi.org/10.1016/s1074-7613(00)80578-6.

    Article  CAS  PubMed  Google Scholar 

  12. Liu D, Xu H, Shih C, Wan Z, Ma X, Ma W, et al. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Nature. 2015;517(7533):214–8. https://doi.org/10.1038/nature13803.

    Article  CAS  PubMed  Google Scholar 

  13. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 2005;435(7041):452–8. https://doi.org/10.1038/nature03555.

    Article  CAS  PubMed  Google Scholar 

  14. Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons JL, et al. Follicular helper T cells are required for systemic autoimmunity. J Exp Med. 2009;206(3):561–76. https://doi.org/10.1084/jem.20081886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Iwai H, Abe M, Hirose S, Tsushima F, Tezuka K, Akiba H, et al. Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis. J Immunol. 2003;171(6):2848–54. https://doi.org/10.4049/jimmunol.171.6.2848.

    Article  CAS  PubMed  Google Scholar 

  16. Kalled SL, Cutler AH, Datta SK, Thomas DW. Anti-CD40 ligand antibody treatment of SNF1 mice with established nephritis: preservation of kidney function. J Immunol. 1998;160(5):2158–65.

    CAS  PubMed  Google Scholar 

  17. Bubier JA, Sproule TJ, Foreman O, Spolski R, Shaffer DJ, Morse HC 3rd, et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci U S A. 2009;106(5):1518–23. https://doi.org/10.1073/pnas.0807309106.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Choi JY, Seth A, Kashgarian M, Terrillon S, Fung E, Huang L, et al. Disruption of pathogenic cellular networks by IL-21 blockade leads to disease amelioration in murine lupus. J Immunol. 2017;198(7):2578–88. https://doi.org/10.4049/jimmunol.1601687.

    Article  CAS  PubMed  Google Scholar 

  19. William J, Euler C, Christensen S, Shlomchik MJ. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science (New York, NY). 2002;297(5589):2066–70. https://doi.org/10.1126/science.1073924.

    Article  Google Scholar 

  20. Odegard JM, Marks BR, DiPlacido LD, Poholek AC, Kono DH, Dong C, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med. 2008;205(12):2873–86. https://doi.org/10.1084/jem.20080840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee SK, Rigby RJ, Zotos D, Tsai LM, Kawamoto S, Marshall JL, et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med. 2011;208(7):1377–88. https://doi.org/10.1084/jem.20102065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21. https://doi.org/10.1016/j.immuni.2010.12.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Choi JY, Ho JH, Pasoto SG, Bunin V, Kim ST, Carrasco S, et al. Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol (Hoboken, NJ). 2015;67(4):988–99. https://doi.org/10.1002/art.39020.

    Article  CAS  Google Scholar 

  24. Zhang X, Lindwall E, Gauthier C, Lyman J, Spencer N, Alarakhia A, et al. Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production. Lupus. 2015;24(9):909–17. https://doi.org/10.1177/0961203314567750.

    Article  CAS  PubMed  Google Scholar 

  25. Liarski VM, Kaverina N, Chang A, Brandt D, Yanez D, Talasnik L, et al. Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci Transl Med. 2014;6(230):230ra46. https://doi.org/10.1126/scitranslmed.3008146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. • Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542(7639):110–4. https://doi.org/10.1038/nature20810This study is the first to demonstrate peripheral T helper, and its potential role in driving B cell maturation in the inflamed tissue.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bocharnikov AV, Keegan J, Wacleche VS, Cao Y, Fonseka CY, Wang G, et al. PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI insight. 2019;4(20). https://doi.org/10.1172/jci.insight.130062.

  28. • Arazi A, Rao DA, Berthier CC, Davidson A, Liu Y, Hoover PJ, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol. 2019;20(7):902–14. https://doi.org/10.1038/s41590-019-0398-xA well-constructed cohort of single-cell RNA-seq of immune cells from patients with lupus nephritis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Espeli M, Bokers S, Giannico G, Dickinson HA, Bardsley V, Fogo AB, et al. Local renal autoantibody production in lupus nephritis. J Am Soc Nephrol. 2011;22(2):296–305. https://doi.org/10.1681/asn.2010050515.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Comte D, Karampetsou MP, Yoshida N, Kis-Toth K, Kyttaris VC, Tsokos GC. Signaling lymphocytic activation molecule family member 7 engagement restores defective effector CD8+ T cell function in systemic lupus erythematosus. Arthritis Rheumatol (Hoboken, NJ). 2017;69(5):1035–44. https://doi.org/10.1002/art.40038.

    Article  CAS  Google Scholar 

  31. Stohl W. Impaired polyclonal T cell cytolytic activity. A possible risk factor for systemic lupus erythematosus. Arthritis Rheum. 1995;38(4):506–16. https://doi.org/10.1002/art.1780380408.

    Article  CAS  PubMed  Google Scholar 

  32. Peng SL, Moslehi J, Robert ME, Craft J. Perforin protects against autoimmunity in lupus-prone mice. J Immunol. 1998;160(2):652–60.

    CAS  PubMed  Google Scholar 

  33. Via CS, Sharrow SO, Shearer GM. Role of cytotoxic T lymphocytes in the prevention of lupus-like disease occurring in a murine model of graft-vs-host disease. J Immunol. 1987;139(6):1840–9.

    CAS  PubMed  Google Scholar 

  34. Kang I, Quan T, Nolasco H, Park SH, Hong MS, Crouch J, et al. Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J Immunol. 2004;172(2):1287–94. https://doi.org/10.4049/jimmunol.172.2.1287.

    Article  CAS  PubMed  Google Scholar 

  35. Larsen M, Sauce D, Deback C, Arnaud L, Mathian A, Miyara M, et al. Exhausted cytotoxic control of Epstein-Barr virus in human lupus. PLoS Pathog. 2011;7(10):e1002328. https://doi.org/10.1371/journal.ppat.1002328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–30. https://doi.org/10.1038/nrrheum.2016.186.

    Article  CAS  PubMed  Google Scholar 

  37. Kis-Toth K, Comte D, Karampetsou MP, Kyttaris VC, Kannan L, Terhorst C, et al. Selective loss of signaling lymphocytic activation molecule family member 4-positive CD8+ T cells contributes to the decreased cytotoxic cell activity in systemic lupus erythematosus. Arthritis Rheumatol (Hoboken, NJ). 2016;68(1):164–73. https://doi.org/10.1002/art.39410.

    Article  CAS  Google Scholar 

  38. • Katsuyama E, Suarez-Fueyo A, Bradley SJ, Mizui M, Marin AV, Mulki L, et al. The CD38/NAD/SIRTUIN1/EZH2 axis mitigates cytotoxic CD8 T cell function and identifies patients with SLE prone to infections. Cell Rep. 2020;30(1):112–23.e4. https://doi.org/10.1016/j.celrep.2019.12.014This study nicely links CD38 with CD8+ T cell exhaustion and risk of infection in lupus patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med. 2020;383(12):1149–55. https://doi.org/10.1056/NEJMoa2023325.

    Article  CAS  PubMed  Google Scholar 

  40. Tilstra JS, Avery L, Menk AV, Gordon RA, Smita S, Kane LP, et al. Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted. J Clin Invest. 2018;128(11):4884–97. https://doi.org/10.1172/jci120859.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido EER, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121–31. https://doi.org/10.1002/art.10461.

    Article  CAS  PubMed  Google Scholar 

  42. • Chen PM, Wilson PC, Shyer JA, Veselits M, Steach HR, Cui C et al. Kidney tissue hypoxia dictates T cell-mediated injury in murine lupus nephritis. Sci Transl Med. 2020;12(538). doi:https://doi.org/10.1126/scitranslmed.aay1620. This is the first study to discuss how inflammatory microenvironment can affect T cell phenotype in promoting tissue damage, and this maladaptation can be intervened to reverse organ damage.

  43. Kapitsinou PP, Sano H, Michael M, Kobayashi H, Davidoff O, Bian A, et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J Clin Invest. 2014;124(6):2396–409. https://doi.org/10.1172/jci69073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Couzi L, Merville P, Deminiere C, Moreau JF, Combe C, Pellegrin JL, et al. Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis. Arthritis Rheum. 2007;56(7):2362–70. https://doi.org/10.1002/art.22654.

    Article  CAS  PubMed  Google Scholar 

  45. Zhou M, Guo C, Li X, Huang Y, Li M, Zhang T, et al. JAK/STAT signaling controls the fate of CD8(+)CD103(+) tissue-resident memory T cell in lupus nephritis. J Autoimmun. 2020;109:102424. https://doi.org/10.1016/j.jaut.2020.102424.

    Article  CAS  PubMed  Google Scholar 

  46. Woltman AM, de Haij S, Boonstra JG, Gobin SJ, Daha MR, van Kooten C. Interleukin-17 and CD40-ligand synergistically enhance cytokine and chemokine production by renal epithelial cells. J Am Soc Nephrol. 2000;11(11):2044–55.

    CAS  PubMed  Google Scholar 

  47. Koga T, Hedrich CM, Mizui M, Yoshida N, Otomo K, Lieberman LA, et al. CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. J Clin Invest. 2014;124(5):2234–45. https://doi.org/10.1172/jci73411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Otomo K, Koga T, Mizui M, Yoshida N, Kriegel C, Bickerton S, et al. Cutting edge: nanogel-based delivery of an inhibitor of CaMK4 to CD4+ T cells suppresses experimental autoimmune encephalomyelitis and lupus-like disease in mice. J Immunol. 2015;195(12):5533–7. https://doi.org/10.4049/jimmunol.1501603.

    Article  CAS  PubMed  Google Scholar 

  49. Koga T, Ichinose K, Mizui M, Crispín JC, Tsokos GC. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J Immunol. 2012;189(7):3490–6. https://doi.org/10.4049/jimmunol.1201785.

    Article  CAS  PubMed  Google Scholar 

  50. Liu Y, Liao J, Zhao M, Wu H, Yung S, Chan TM, et al. Increased expression of TLR2 in CD4(+) T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications. Eur J Immunol. 2015;45(9):2683–93. https://doi.org/10.1002/eji.201445219.

    Article  CAS  PubMed  Google Scholar 

  51. Apostolidis SA, Rauen T, Hedrich CM, Tsokos GC, Crispín JC. Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling. J Biol Chem. 2013;288(37):26775–84. https://doi.org/10.1074/jbc.M113.483743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sunahori K, Nagpal K, Hedrich CM, Mizui M, Fitzgerald LM, Tsokos GC. The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients. J Biol Chem. 2013;288(30):21936–44. https://doi.org/10.1074/jbc.M113.467266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. • Choi SC, Brown J, Gong M, Ge Y, Zadeh M, Li W, et al. Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice. Sci Transl Med. 2020;12(551). https://doi.org/10.1126/scitranslmed.aax2220A very nice illustration of how microbiota and altered metabolism contribute to lupus pathogenesis.

  54. Crispin JC, Tsokos GC. Interleukin-17-producing T cells in lupus. Curr Opin Rheumatol. 2010;22(5):499–503. https://doi.org/10.1097/BOR.0b013e32833c62b0.

    Article  CAS  PubMed  Google Scholar 

  55. Zhou XJ, Mu R, Li C, Nath SK, Zhang YM, Qi YY, et al. Association of variants in CCR6 with susceptibility to lupus nephritis in Chinese. Arthritis Rheumatol (Hoboken, NJ). 2015;67(11):3091–3. https://doi.org/10.1002/art.39268.

    Article  Google Scholar 

  56. Poissonnier A, Sanseau D, Le Gallo M, Malleter M, Levoin N, Viel R, et al. CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice. Immunity. 2016;45(1):209–23. https://doi.org/10.1016/j.immuni.2016.06.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Krebs CF, Reimers D, Zhao Y, Paust HJ, Bartsch P, Nuñez S, et al. Pathogen-induced tissue-resident memory T(H)17 (T(RM)17) cells amplify autoimmune kidney disease. Sci Immunol. 2020;5(50). https://doi.org/10.1126/sciimmunol.aba4163.

  58. Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008;181(12):8761–6. https://doi.org/10.4049/jimmunol.181.12.8761.

    Article  CAS  PubMed  Google Scholar 

  59. Lai ZW, Borsuk R, Shadakshari A, Yu J, Dawood M, Garcia R, et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J Immunol. 2013;191(5):2236–46. https://doi.org/10.4049/jimmunol.1301005.

    Article  CAS  PubMed  Google Scholar 

  60. Hedrich CM, Rauen T, Crispin JC, Koga T, Ioannidis C, Zajdel M, et al. cAMP-responsive element modulator α (CREMα) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4-CD8- T cells in health and disease. J Biol Chem. 2013;288(44):31880–7. https://doi.org/10.1074/jbc.M113.508655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rodríguez-Rodríguez N, Apostolidis SA, Fitzgerald L, Meehan BS, Corbett AJ, Martín-Villa JM, et al. Pro-inflammatory self-reactive T cells are found within murine TCR-αβ(+) CD4(−) CD8(−) PD-1(+) cells. Eur J Immunol. 2016;46(6):1383–91. https://doi.org/10.1002/eji.201546056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Amarilyo G, Lourenco EV, Shi FD, La Cava A. IL-17 promotes murine lupus. J Immunol. 2014;193(2):540–3. https://doi.org/10.4049/jimmunol.1400931.

    Article  CAS  PubMed  Google Scholar 

  63. Schmidt T, Paust HJ, Krebs CF, Turner JE, Kaffke A, Bennstein SB, et al. Function of the Th17/interleukin-17A immune response in murine lupus nephritis. Arthritis Rheumatol (Hoboken, NJ). 2015;67(2):475–87. https://doi.org/10.1002/art.38955.

    Article  CAS  Google Scholar 

  64. Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, et al. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum. 1999;42(8):1644–8. https://doi.org/10.1002/1529-0131(199908)42:8<1644::aid-anr12>3.0.co;2-l.

    Article  CAS  PubMed  Google Scholar 

  65. Okamoto A, Fujio K, Tsuno NH, Takahashi K, Yamamoto K. Kidney-infiltrating CD4+ T-cell clones promote nephritis in lupus-prone mice. Kidney Int. 2012;82(9):969–79. https://doi.org/10.1038/ki.2012.242.

    Article  CAS  PubMed  Google Scholar 

  66. Schwarting A, Wada T, Kinoshita K, Tesch G, Kelley VR. IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas(lpr) mice. J Immunol. 1998;161(1):494–503.

    CAS  PubMed  Google Scholar 

  67. Kikawada E, Lenda DM, Kelley VR. IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. J Immunol. 2003;170(7):3915–25.

    Article  CAS  PubMed  Google Scholar 

  68. Enghard P, Humrich JY, Rudolph B, Rosenberger S, Biesen R, Kuhn A, et al. CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients. Arthritis Rheum. 2009;60(1):199–206. https://doi.org/10.1002/art.24136.

    Article  CAS  PubMed  Google Scholar 

  69. Richards HB, Satoh M, Jennette JC, Croker BP, Yoshida H, Reeves WH. Interferon-gamma is required for lupus nephritis in mice treated with the hydrocarbon oil pristane. Kidney Int. 2001;60(6):2173–80. https://doi.org/10.1046/j.1523-1755.2001.00045.x.

    Article  CAS  PubMed  Google Scholar 

  70. Steinmetz OM, Turner JE, Paust HJ, Lindner M, Peters A, Heiss K, et al. CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis. J Immunol. 2009;183(7):4693–704. https://doi.org/10.4049/jimmunol.0802626.

    Article  CAS  PubMed  Google Scholar 

  71. Lee SK, Silva DG, Martin JL, Pratama A, Hu X, Chang PP, et al. Interferon-γ excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity. 2012;37(5):880–92. https://doi.org/10.1016/j.immuni.2012.10.010.

    Article  CAS  PubMed  Google Scholar 

  72. Boedigheimer MJ, Martin DA, Amoura Z, Sánchez-Guerrero J, Romero-Diaz J, Kivitz A, et al. Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis. Lupus Sci Med. 2017;4(1):e000226. https://doi.org/10.1136/lupus-2017-000226.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med. 2005;202(10):1387–97. https://doi.org/10.1084/jem.20051409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J, et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013;121(9):1595–603. https://doi.org/10.1182/blood-2012-09-457465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87. https://doi.org/10.1016/j.cell.2008.05.009.

    Article  CAS  PubMed  Google Scholar 

  76. Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI. Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol. 2006;177(3):1451–9. https://doi.org/10.4049/jimmunol.177.3.1451.

    Article  CAS  PubMed  Google Scholar 

  77. Weigert O, von Spee C, Undeutsch R, Kloke L, Humrich JY, Riemekasten G. CD4+Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZBxNZW) F1 lupus mice. Arthritis Res Therapy. 2013;15(1):R35. https://doi.org/10.1186/ar4188.

    Article  CAS  Google Scholar 

  78. Humrich JY, Morbach H, Undeutsch R, Enghard P, Rosenberger S, Weigert O, et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci U S A. 2010;107(1):204–9. https://doi.org/10.1073/pnas.0903158107.

    Article  PubMed  Google Scholar 

  79. Divekar AA, Dubey S, Gangalum PR, Singh RR. Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu. J Immunol. 2011;186(2):924–30. https://doi.org/10.4049/jimmunol.1002218.

    Article  CAS  PubMed  Google Scholar 

  80. Parietti V, Monneaux F, Décossas M, Muller S. Function of CD4+,CD25+ Treg cells in MRL/lpr mice is compromised by intrinsic defects in antigen-presenting cells and effector T cells. Arthritis Rheum. 2008;58(6):1751–61. https://doi.org/10.1002/art.23464.

    Article  CAS  PubMed  Google Scholar 

  81. Bonelli M, Savitskaya A, von Dalwigk K, Steiner CW, Aletaha D, Smolen JS, et al. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int Immunol. 2008;20(7):861–8. https://doi.org/10.1093/intimm/dxn044.

    Article  CAS  PubMed  Google Scholar 

  82. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579–88. https://doi.org/10.4049/jimmunol.178.4.2579.

    Article  CAS  PubMed  Google Scholar 

  83. Vargas-Rojas MI, Crispín JC, Richaud-Patin Y, Alcocer-Varela J. Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus. 2008;17(4):289–94. https://doi.org/10.1177/0961203307088307.

    Article  CAS  PubMed  Google Scholar 

  84. Venigalla RK, Tretter T, Krienke S, Max R, Eckstein V, Blank N, et al. Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high,CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 2008;58(7):2120–30. https://doi.org/10.1002/art.23556.

    Article  PubMed  Google Scholar 

  85. Costa N, Marques O, Godinho SI, Carvalho C, Leal B, Figueiredo AM, et al. Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives. Clin Exp Immunol. 2017;189(3):318–30. https://doi.org/10.1111/cei.12991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–3. https://doi.org/10.1038/nm.4148.

    Article  CAS  PubMed  Google Scholar 

  87. Apostolidis SA, Rodríguez-Rodríguez N, Suárez-Fueyo A, Dioufa N, Ozcan E, Crispín JC, et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat Immunol. 2016;17(5):556–64. https://doi.org/10.1038/ni.3390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, et al. Foxp3 and toll-like receptor signaling balance T(reg) cell anabolic metabolism for suppression. Nat Immunol. 2016;17(12):1459–66. https://doi.org/10.1038/ni.3577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yin Y, Choi SC, Xu Z, Perry DJ, Seay H, Croker BP, et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med. 2015;7(274):274ra18. https://doi.org/10.1126/scitranslmed.aaa0835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dall'Era M, Pauli ML, Remedios K, Taravati K, Sandova PM, Putnam AL, et al. Adoptive Treg cell therapy in a patient with systemic lupus erythematosus. Arthritis Rheumatol (Hoboken, NJ). 2019;71(3):431–40. https://doi.org/10.1002/art.40737.

    Article  CAS  Google Scholar 

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  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Ping-Min Chen & George C. Tsokos

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Ping-Min Chen wrote the manuscript. George Tsokos supervised and revised the manuscript.

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Chen, PM., Tsokos, G.C. T Cell Abnormalities in the Pathogenesis of Systemic Lupus Erythematosus: an Update. Curr Rheumatol Rep 23, 12 (2021). https://doi.org/10.1007/s11926-020-00978-5

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