Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Immunological memory in rheumatic inflammation — a roadblock to tolerance induction

Abstract

Why do we still have no cure for chronic inflammatory diseases? One reason could be that current therapies are based on the assumption that chronic inflammation is driven by persistent ‘acute’ immune reactions. Here we discuss a paradigm shift by suggesting that beyond these reactions, chronic inflammation is driven by imprinted, pathogenic ‘memory’ cells of the immune system. This rationale is based on the observation that in patients with chronic inflammatory rheumatic diseases refractory to conventional immunosuppressive therapies, therapy-free remission can be achieved by resetting the immune system; that is, by ablating immune cells and regenerating the immune system from stem cells. The success of this approach identifies antigen-experienced and imprinted immune cells as essential and sufficient drivers of inflammation. The ‘dark side’ of immunological memory primarily involves memory plasma cells secreting pathogenic antibodies and memory T lymphocytes secreting pathogenic cytokines and chemokines, but can also involve cells of innate immunity. New therapeutic strategies should address the persistence of these memory cells. Selective targeting of pathogenic immune memory cells could be based on their specificity, which is challenging, or on their lifestyle, which differs from that of protective immune memory cells, in particular for pathogenic T lymphocytes. The adaptations of such pathogenic memory cells to chronic inflammation offers entirely new therapeutic options for their selective ablation and the regeneration of immunological tolerance.

Key points

  • Chronic inflammatory rheumatic diseases are driven by long-lived, adapted memory cells: memory plasma cells, memory B and T lymphocytes and imprinted innate cells.

  • Memory cells have passed all physiological tolerance checkpoints; they are refractory to conventional therapeutic efforts that aim to restore tolerance.

  • Elimination of pathogenic memory cells is a prerequisite for the restoration of immunological tolerance and achievement of therapy-free remission.

  • Analysis of transcriptomes and physiology of pathogenic memory cells has revealed novel therapeutic candidate targets for their selective elimination and suggests that combination therapies could be relevant.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Pathogenic memory cells are beyond tolerance checkpoints.
Fig. 2: The lifestyle of protective and pathogenic memory lymphocytes differs fundamentally.
Fig. 3: The bone marrow plasma cell niche as a putative therapeutic target for the depletion of (pathogenic) memory plasma cells.
Fig. 4: Plasticity of T helper lymphocytes in chronic inflammation.
Fig. 5: Molecular adaptations of repeatedly activated TH1 cells of chronic inflammation.

References

  1. 1.

    von Behring, E. Ueber das zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. (Philipps-Universität Marburg, 1890).

  2. 2.

    Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Landsverk, O. J. et al. Antibody-secreting plasma cells persist for decades in human intestine. J. Exp. Med. 214, 309–317 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Hammarlund, E. et al. Plasma cell survival in the absence of B cell memory. Nat. Commun. 8, 1781 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Okumura, K., Julius, M. H., Tsu, T. & Herzenberg, L. A. Demonstration that IgG memory is carried by IgG-bearing cells. Eur. J. Immunol. 6, 467–472 (1976).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Rogers, P. R., Dubey, C. & Swain, S. L. Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen. J. Immunol. 164, 2338–2346 (2000).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Zinkernagel, R. M. On differences between immunity and immunological memory. Curr. Opin. Immunol. 14, 523–536 (2002).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Tykocinski, L. O. et al. A critical control element for interleukin-4 memory expression in T helper lymphocytes. J. Biol. Chem. 280, 28177–28185 (2005).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Dong, J. et al. Loss of methylation at the IFNG promoter and CNS-1 is associated with the development of functional IFN-γ memory in human CD4+ T lymphocytes. Eur. J. Immunol. 43, 793–804 (2013).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Chang, H. D., Tokoyoda, K. & Radbruch, A. Immunological memories of the bone marrow. Immunol. Rev. 283, 86–98 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Di Rosa, F. Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation? Nat. Rev. Immunol. 16, 271 (2016).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Di Rosa, F. & Gebhardt, T. Bone marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells. Front. Immunol. 7, 51 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Giesecke, C. et al. Tissue distribution and dependence of responsiveness of human antigen-specific memory B cells. J. Immunol. 192, 3091–3100 (2014).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Riedel, R. et al. Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow. Nat. Commun. 11, 2570 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Croft, M., Bradley, L. M. & Swain, S. L. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J. Immunol. 152, 2675–2685 (1994).

    CAS  PubMed  Google Scholar 

  20. 20.

    London, C. A., Lodge, M. P. & Abbas, A. K. Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol. 164, 265–272 (2000).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Inoue, T., Moran, I., Shinnakasu, R., Phan, T. G. & Kurosaki, T. Generation of memory B cells and their reactivation. Immunol. Rev. 283, 138–149 (2018).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Netea, M. G., Quintin, J. & van der Meer, J. W. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361 (2011).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Guo, Q. et al. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 6, 15 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Romao, V. C. & Fonseca, J. E. Major challenges in rheumatology: will we ever treat smarter, instead of just harder? Front. Med. 6, 144 (2019).

    Article  Google Scholar 

  27. 27.

    Mangoni, A. A. et al. Relapse rates after elective discontinuation of anti-TNF therapy in rheumatoid arthritis: a meta-analysis and review of literature. BMC Rheumatol. 3, 10 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Alexander, T. et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113, 214–223 (2009).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Alexander, T. et al. Hematopoietic stem cell therapy for autoimmune diseases — clinical experience and mechanisms. J. Autoimmun. 92, 35–46 (2018).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    King, C., Ilic, A., Koelsch, K. & Sarvetnick, N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265–277 (2004).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Burt, R. K. et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 313, 275–284 (2015).

    PubMed  Article  Google Scholar 

  32. 32.

    Fagraeus, A. Plasma cellular reaction and its relation to the formation of antibodies in vitro. Nature 159, 499 (1947).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Cooper, M. D., Peterson, R. D. & Good, R. A. Delineation of the thymic and bursal lymphoid systems in the chicken. Nature 205, 143–146 (1965).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Cavelti, P. A. Autoantibodies in rheumatic fever. Proc. Soc. Exp. Biol. Med. 60, 379–381 (1945).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Gear, J. Autoantigens and autoantibodies in the pathogenesis of disease with special refenence to blackwater fever. Trans. R. Soc. Trop. Med. Hyg. 39, 301–314 (1945).

    PubMed  Article  Google Scholar 

  36. 36.

    Mackay, I. R. Travels and travails of autoimmunity: a historical journey from discovery to rediscovery. Autoimmun. Rev. 9, A251–258 (2010).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Suurmond, J. & Diamond, B. Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J. Clin. Invest. 125, 2194–2202 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Hansen, I. S., Baeten, D. L. P. & den Dunnen, J. The inflammatory function of human IgA. Cell Mol. Life Sci. 76, 1041–1055 (2019).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Kubagawa, H. et al. Functional roles of the IgM Fc receptor in the immune system. Front. Immunol. 10, 945 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Ochsenbein, A. F. et al. Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs. Proc. Natl Acad. Sci. USA 97, 13263–13268 (2000).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Nossal, G. J. Antibody production by single cells. III. The histology of antibody production. Br. J. Exp. Pathol. 40, 301–311 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Benner, R., Meima, F., van der Meulen, G. M. & van Muiswinkel, W. B. Antibody formation in mouse bone marrow. I. Evidence for the development of plaque-forming cells in situ. Immunology 26, 247–255 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Manz, R. A., Lohning, M., Cassese, G., Thiel, A. & Radbruch, A. Survival of long-lived plasma cells is independent of antigen. Int. Immunol. 10, 1703–1711 (1998).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Farber, D. L., Netea, M. G., Radbruch, A., Rajewsky, K. & Zinkernagel, R. M. Immunological memory: lessons from the past and a look to the future. Nat. Rev. Immunol. 16, 124–128 (2016).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Hoyer, B. F. et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577–1584 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Cheng, Q. et al. Autoantibodies from long-lived ‘memory’ plasma cells of NZB/W mice drive immune complex nephritis. Ann. Rheum. Dis. 72, 2011–2017 (2013).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Cambridge, G. et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 48, 2146–2154 (2003).

    PubMed  Article  Google Scholar 

  50. 50.

    Ferraro, A. J., Drayson, M. T., Savage, C. O. & MacLennan, I. C. Levels of autoantibodies, unlike antibodies to all extrinsic antigen groups, fall following B cell depletion with rituximab. Eur. J. Immunol. 38, 292–298 (2008).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Hiepe, F. et al. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7, 170–178 (2011).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Jonsdottir, T. et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann. Rheum. Dis. 67, 330–334 (2008).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Mumtaz, I. M. et al. Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: implications for the treatment of autoimmunity. J. Autoimmun. 39, 180–188 (2012).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Hiepe, F. & Radbruch, A. Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat. Rev. Nephrol. 12, 232–240 (2016).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Chang, H. D. et al. Pathogenic memory plasma cells in autoimmunity. Curr. Opin. Immunol. 61, 86–91 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Manz, R. A. & Radbruch, A. Plasma cells for a lifetime? Eur. J. Immunol. 32, 923–927 (2002).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Cassese, G. et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 171, 1684–1690 (2003).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Cassese, G. et al. Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 31, 2726–2732 (2001).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Starke, C. et al. High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice. Eur. J. Immunol. 41, 2107–2112 (2011).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Hauser, A. E. et al. Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J. Immunol. 169, 1277–1282 (2002).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Muehlinghaus, G. et al. Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells. Blood 105, 3965–3971 (2005).

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Odendahl, M. et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 105, 1614–1621 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Mei, H. E. et al. Blood-borne human plasma cells in steady state are derived from mucosal immune responses. Blood 113, 2461–2469 (2009).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Addo, R. K. et al. Single-cell transcriptomes of murine bone marrow stromal cells reveal niche-associated heterogeneity. Eur. J. Immunol. 49, 1372–1379 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943–952 (2004).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Cheng, Q. et al. CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice. Eur. J. Immunol. 48, 1020–1029 (2018).

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    O’Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Peperzak, V. et al. Mcl-1 is essential for the survival of plasma cells. Nat. Immunol. 14, 290–297 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Zehentmeier, S. et al. Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells. Eur. J. Immunol. 44, 2306–2317 (2014).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    van Spriel, A. B. et al. The tetraspanin CD37 orchestrates the α4β1 integrin-Akt signaling axis and supports long-lived plasma cell survival. Sci. Signal. 5, ra82 (2012).

    PubMed  Google Scholar 

  71. 71.

    Auner, H. W., Beham-Schmid, C., Dillon, N. & Sabbattini, P. The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress. Blood 116, 3445–3455 (2010).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Cornelis, R. et al. Stromal cell-contact dependent PI3K and APRIL induced NF-κB signaling prevent mitochondrial- and ER stress induced death of memory plasma cells. Cell Rep. 32, 107982 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    DiLillo, D. J. et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 180, 361–371 (2008).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Manne, C. et al. Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow. Proc. Natl Acad. Sci. USA 116, 7425–7430 (2019).

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Xiang, Z. et al. FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nat. Immunol. 8, 419–429 (2007).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Manz, R., Assenmacher, M., Pfluger, E., Miltenyi, S. & Radbruch, A. Analysis and sorting of live cells according to secreted molecules, relocated to a cell-surface affinity matrix. Proc. Natl Acad. Sci. USA 92, 1921–1925 (1995).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Taddeo, A. et al. Selection and depletion of plasma cells based on the specificity of the secreted antibody. Eur. J. Immunol. 45, 317–319 (2015).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Cheng, Q. et al. Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies. Eur. J. Immunol. (2019).

  79. 79.

    Hofmann, K., Clauder, A. K. & Manz, R. A. Targeting B cells and plasma cells in autoimmune diseases. Front. Immunol. 9, 835 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Alexander, T. et al. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann. Rheum. Dis. 74, 1474–1478 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Alexander, T. et al. Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. Eur. J. Immunol. 48, 1573–1579 (2018).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Ostendorf, L. et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N. Engl. J. Med. 383, 1149–1155 (2020).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Khodadadi, L. et al. Bortezomib plus continuous B cell depletion results in sustained plasma cell depletion and amelioration of lupus nephritis in NZB/W F1 mice. PLoS One 10, e0135081 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Taddeo, A. et al. Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors. Arthritis Res. Ther. 17, 39 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Macauley, M. S. et al. Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis. J. Clin. Invest. 123, 3074–3083 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Li, R. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 7, 310ra166 (2015).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3, 944–950 (2002).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Lino, A. C. et al. LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity 49, 120–133.e9 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Duddy, M. et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J. Immunol. 178, 6092–6099 (2007).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Alp, O. S. & Radbruch, A. The lifestyle of memory CD8+ T cells. Nat. Rev. Immunol. 16, 271 (2016).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    McGregor, D. D. & Gowans, J. L. The antibody response of rats depleted of lymphocytes by chronic drainage from the thoracic duct. J. Exp. Med. 117, 303–320 (1963).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Mueller, S. N., Gebhardt, T., Carbone, F. R. & Heath, W. R. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137–161 (2013).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Tokoyoda, K. et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30, 721–730 (2009).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Okhrimenko, A. et al. Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory. Proc. Natl Acad. Sci. USA 111, 9229–9234 (2014).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Di Rosa, F. & Pabst, R. The bone marrow: a nest for migratory memory T cells. Trends Immunol. 26, 360–366 (2005).

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Siracusa, F. et al. Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation. Eur. J. Immunol. 47, 1900–1905 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Siracusa, F. et al. CD69+ memory T lymphocytes of the bone marrow and spleen express the signature transcripts of tissue-resident memory T lymphocytes. Eur. J. Immunol. 49, 966–968 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Walsh, D. A. et al. The functional requirement for CD69 in establishment of resident memory CD8+ T cells varies with tissue location. J. Immunol. 203, 946–955 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Shiow, L. R. et al. CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Bankovich, A. J., Shiow, L. R. & Cyster, J. G. CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4. J. Biol. Chem. 285, 22328–22337 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Shinoda, K. et al. Type II membrane protein CD69 regulates the formation of resting T-helper memory. Proc. Natl Acad. Sci. USA 109, 7409–7414 (2012).

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Hayashizaki, K. et al. Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation. Sci. Immunol. 1, eaaf9154 (2016).

    PubMed  Article  Google Scholar 

  111. 111.

    Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Siracusa, F. et al. Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc. Natl Acad. Sci. USA 115, 1334–1339 (2018).

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Dijkgraaf, F. E. et al. Tissue patrol by resident memory CD8+ T cells in human skin. Nat. Immunol. 20, 756–764 (2019).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Sercan Alp, O. et al. Memory CD8+ T cells colocalize with IL-7+ stromal cells in bone marrow and rest in terms of proliferation and transcription. Eur. J. Immunol. 45, 975–987 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Allie, S. R. et al. The establishment of resident memory B cells in the lung requires local antigen encounter. Nat. Immunol. 20, 97–108 (2019).

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Mamani-Matsuda, M. et al. The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells. Blood 111, 4653–4659 (2008).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Martinez-Gamboa, L. et al. Role of the spleen in peripheral memory B-cell homeostasis in patients with autoimmune thrombocytopenia purpura. Clin. Immunol. 130, 199–212 (2009).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Schulz, E. G., Mariani, L., Radbruch, A. & Hofer, T. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-γ and interleukin-12. Immunity 30, 673–683 (2009).

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Richter, A., Lohning, M. & Radbruch, A. Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell cycle progression. J. Exp. Med. 190, 1439–1450 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Lohning, M., Richter, A. & Radbruch, A. Cytokine memory of T helper lymphocytes. Adv. Immunol. 80, 115–181 (2002).

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Stittrich, A. B. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat. Immunol. 11, 1057–1062 (2010).

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Obst, R., van Santen, H. M., Mathis, D. & Benoist, C. Antigen persistence is required throughout the expansion phase of a CD4+ T cell response. J. Exp. Med. 201, 1555–1565 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Rabenstein, H. et al. Differential kinetics of antigen dependency of CD4+ and CD8+ T cells. J. Immunol. 192, 3507–3517 (2014).

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Assenmacher, M. et al. Sequential production of IL-2, IFN-γ and IL-10 by individual staphylococcal enterotoxin B-activated T helper lymphocytes. Eur. J. Immunol. 28, 1534–1543 (1998).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Assenmacher, M., Schmitz, J. & Radbruch, A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-γ and in interleukin-4-expressing cells. Eur. J. Immunol. 24, 1097–1101 (1994).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Lohning, M. et al. Establishment of memory for IL-10 expression in developing T helper 2 cells requires repetitive IL-4 costimulation and does not impair proliferation. Proc. Natl Acad. Sci. USA 100, 12307–12312 (2003).

    PubMed  Article  CAS  Google Scholar 

  128. 128.

    Rutz, S. et al. Notch regulates IL-10 production by T helper 1 cells. Proc. Natl Acad. Sci. USA 105, 3497–3502 (2008).

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Gagliani, N. et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Chang, H. D. et al. Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur. J. Immunol. 37, 807–817 (2007).

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Peine, M. et al. Stable T-bet+GATA-3+ Th1/Th2 hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation. PLoS Biol. 11, e1001633 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Hwang, E. S., Hong, J. H. & Glimcher, L. H. IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508. J. Exp. Med. 202, 1289–1300 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    von Spee-Mayer, C. et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 75, 1407–1415 (2016).

    Article  CAS  Google Scholar 

  136. 136.

    Humrich, J. Y. et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc. Natl Acad. Sci. USA 107, 204–209 (2010).

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    de la Rosa, M., Rutz, S., Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480–2488 (2004).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  138. 138.

    Black, A. P., Bhayani, H., Ryder, C. A., Gardner-Medwin, J. M. & Southwood, T. R. T-cell activation without proliferation in juvenile idiopathic arthritis. Arthritis Res. 4, 177–183 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Frenz, T. et al. CD4+ T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion. J. Allergy Clin. Immunol. 138, 586–589.e10 (2016).

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Niesner, U. et al. Autoregulation of Th1-mediated inflammation by twist1. J. Exp. Med. 205, 1889–1901 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Albrecht, I. et al. Persistence of effector memory Th1 cells is regulated by Hopx. Eur. J. Immunol. 40, 2993–3006 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  142. 142.

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

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991–999 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Mazzoni, A. et al. Eomes controls the development of Th17-derived (non-classic) Th1 cells during chronic inflammation. Eur. J. Immunol. 49, 79–95 (2019).

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Zimmermann, J. et al. T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis. Mucosal Immunol. 9, 1487–1499 (2016).

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Rebhahn, J. A. et al. An animated landscape representation of CD4+ T-cell differentiation, variability, and plasticity: insights into the behavior of populations versus cells. Eur. J. Immunol. 44, 2216–2229 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Neurath, M. F. et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J. Exp. Med. 195, 1129–1143 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Hildner, K. M. et al. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J. Immunol. 178, 3427–3436 (2007).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Miossec, P. Diseases that may benefit from manipulating the Th17 pathway. Eur. J. Immunol. 39, 667–669 (2009).

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Dardalhon, V., Korn, T., Kuchroo, V. K. & Anderson, A. C. Role of Th1 and Th17 cells in organ-specific autoimmunity. J. Autoimmun. 31, 252–256 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Zimmermann, J. et al. The intestinal microbiota determines the colitis-inducing potential of T-bet-deficient Th cells in mice. Eur. J. Immunol. 48, 161–167 (2018).

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Lexberg, M. H. et al. IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur. J. Immunol. 40, 3017–3027 (2010).

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Bending, D. et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J. Clin. Invest. 119, 565–572 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Mazzoni, A. et al. Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclassic Th1 cells. J. Immunol. 194, 3116–3126 (2015).

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Myles, A., Gearhart, P. J. & Cancro, M. P. Signals that drive T-bet expression in B cells. Cell Immunol. 321, 3–7 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Johnson, J. L., Scholz, J. L., Marshak-Rothstein, A. & Cancro, M. P. Molecular pattern recognition in peripheral B cell tolerance: lessons from age-associated B cells. Curr. Opin. Immunol. 61, 33–38 (2019).

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Pham, D., Vincentz, J. W., Firulli, A. B. & Kaplan, M. H. Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function. J. Immunol. 189, 832–840 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Haftmann, C. et al. miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim. Eur. J. Immunol. 45, 1192–1205 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Maschmeyer, P. et al. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J. Autoimmun. 89, 41–52 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Hradilkova, K. et al. Regulation of fatty acid oxidation by Twist 1 in the metabolic adaptation of T helper lymphocytes to chronic inflammation. Arthritis Rheumatol. 71, 1756–1765 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Fonseka, C. Y. et al. Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis. Sci. Transl. Med. 10, eaaq0305 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164.

    Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. 165.

    Arazi, A. et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat. Immunol. 20, 902–914 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Maschmeyer, P. et al. Antigen-driven PD-1+TOX+EOMES+ and PD-1+ TOX+ BHLHE40+ synovial T lymphocytes regulate chronic inflammation in situ. Eur. J. Immunol. https://doi.org/10.1002/eji.202048797 (2020).

    Article  PubMed  Google Scholar 

  167. 167.

    Bardua, M. et al. MicroRNA-31 reduces the motility of proinflammatory T helper 1 lymphocytes. Front. Immunol. 9, 2813 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Petrelli, A. et al. PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation. J. Clin. Invest. 128, 4669–4681 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Kock, J. et al. Nuclear factor of activated T cells regulates the expression of interleukin-4 in Th2 cells in an all-or-none fashion. J. Biol. Chem. 289, 26752–26761 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  170. 170.

    Podtschaske, M. et al. Digital NFATc2 activation per cell transforms graded T cell receptor activation into an all-or-none IL-2 expression. PLoS One 2, e935 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171.

    Luetke-Eversloh, M. et al. Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLoS Pathog. 10, e1004441 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. 172.

    Babic, M. & Romagnani, C. The role of natural killer group 2, member D in chronic inflammation and autoimmunity. Front. Immunol. 9, 1219 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. 173.

    Gronke, K. et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566, 249–253 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2016).

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Cronk, J. C. et al. Methyl-CpG binding protein 2 regulates microglia and macrophage gene expression in response to inflammatory stimuli. Immunity 42, 679–691 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Triantafyllopoulou, A. et al. Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc. Natl Acad. Sci. USA 107, 3012–3017 (2010).

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Arts, R. J. W., Joosten, L. A. B. & Netea, M. G. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9, 298 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. 180.

    Pap, T. et al. Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum. 43, 1226–1232 (2000).

    CAS  PubMed  Article  Google Scholar 

  181. 181.

    Eljaafari, A. et al. Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: contribution to the chronicity of rheumatoid arthritis. Arthritis Rheum. 64, 2147–2157 (2012).

    CAS  PubMed  Article  Google Scholar 

  182. 182.

    Muller-Ladner, U. et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607–1615 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Moore, J. et al. A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe, refractory rheumatoid arthritis. Arthritis Rheum. 46, 2301–2309 (2002).

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Wei, K. et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 582, 259–264 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Aungier, S. R. et al. Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy? Ann. Rheum. Dis. 78, 186–191 (2019).

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Siebert, S. et al. Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: an early phase trial. Medicine 99, e20458 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018).

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Dominguez-Andres, J., Fanucchi, S., Joosten, L. A. B., Mhlanga, M. M. & Netea, M. G. Advances in understanding molecular regulation of innate immune memory. Curr. Opin. Cell Biol. 63, 68–75 (2020).

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Sekine, C. et al. Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors. J. Immunol. 180, 1954–1961 (2008).

    CAS  PubMed  Article  Google Scholar 

  191. 191.

    Scheibe, F. et al. Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis. J. Neurol. 267, 317–323 (2020).

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    Scheibe, F. et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology 88, 366–370 (2017).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Kohler, S. et al. Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial. BMJ Open 9, e024523 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Pontarini, E. et al. Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjogren’s syndrome. Rheumatology 54, 1429–1434 (2015).

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Stohl, W. et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 69, 1016–1027 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 196.

    Doria, A. et al. Efficacy and safety of subcutaneous belimumab in anti-double-stranded DNA-positive, hypocomplementemic patients with systemic lupus erythematosus. Arthritis Rheumatol. 70, 1256–1264 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    van Vollenhoven, R. F. et al. Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension. Rheumatology 59, 281–291 (2020).

    PubMed  Article  CAS  Google Scholar 

  198. 198.

    Zhang, F. et al. A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea. Ann. Rheum. Dis. 77, 355–363 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Hewett, K. et al. Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis. Neurology 90, e1425–e1434 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Kraaij, T. et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J. Autoimmun. 91, 45–54 (2018).

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Merrill, J. T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study. Arthritis Rheumatol. 70, 266–276 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Morand, E. F. et al. Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study. Rheumatology 59, 2930–2938 (2020).

    PubMed  Article  Google Scholar 

  203. 203.

    He, J. et al. Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus. Nat. Med. 22, 991–993 (2016).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the European Research Council Advanced Grant IMMEMO (ERC-2010-AdG.20100317 Grant 268987), the Deutsche Forschungsgemeinschaft (TRR130 P16 and P15, and TRR241 B03), Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777357 and no. 831434, the state of Berlin and the European Regional Development Fund (ERDF 2014–2020, EFRE 1.8/11, Deutsches Rheuma-Forschungszentrum Berlin) and the Leibniz ScienceCampus Chronic Inflammation. H.D.C. is supported by the Dr. Rolf M. Schwiete Foundation.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Andreas Radbruch.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Rheumatology thanks V. Malmström and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Specific antigen receptors

Cells of the immune system express millions of different antigen receptors, each of them specifically recognizing particular structures. Each B lymphocyte expresses a particular antibody and each T lymphocyte a particular T cell receptor, enabling them to recognize and react to a defined chemical structure, the antigen.

Immunological tolerance

Ablation or inactivation of B and T lymphocytes with antigen receptors specific for the body’s own and harmless antigens.

Immunological memory

Imprinting and maintenance of the immune cells of an immune reaction when the reaction is over. Memory plasma cells provide protection by secretion of antibodies, and memory B and T lymphocytes provide rapid and enhanced secondary immune reactions.

Homeostatic proliferation

Proliferation of memory lymphocytes induced by cytokines, in the absence of antigen.

Plasma cell niche

A local environment organized by mesenchymal stromal cells, which provides survival signals for memory plasma cells.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Maschmeyer, P., Chang, HD., Cheng, Q. et al. Immunological memory in rheumatic inflammation — a roadblock to tolerance induction. Nat Rev Rheumatol (2021). https://doi.org/10.1038/s41584-021-00601-6

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing