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Restoration of the peace in autoimmune disease: tired of fighting?

Cellular & Molecular Immunology volume 22, pages 1276–1278 (2025)Cite this article

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The Original Article was published on 23 July 2025

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Few topics in T-cell immunology have received as much attention in recent years as the phenomenon known as “exhaustion”. This condition is widely believed to result from excessive repetitive stimulation of T cells, which “exhausts” their ability to perform “effector functions”, such as the production of proinflammatory cytokines, and makes them ineffective in the battle against certain viruses or cancers [1]. Some consider the term “exhaustion” too anthropomorphic and prefer to call this phenomenon “dysfunction” [2]. A study by Bae et al. on this issue of Cellular and Molecular Immunology presented evidence that at least some CD4+ T cells with the characteristics of “exhaustion” are not actually dysfunctional but instead serve a different function, namely, to promote the restoration of immunological tolerance after a temporary breach thereof [3].

The immune system has the delicate task of protecting against pathogens and cancer without causing excessive damage. Healthy tissue must not be attacked, necessitating the existence of mechanisms to ensure self-tolerance. To this end, self-reactive T cells are eliminated during thymic development, whereas regulatory T cells (Tregs) inhibit untoward immune responses via self-reactive T cells that inadvertently escape thymic selection [4]. These mechanisms generally work well, but the existence of autoimmune diseases shows that they are not always perfect. Furthermore, protracted immune responses can cause cumulative tissue damage and, at some point, it may be more beneficial to the fitness of the host to accept the presence of an invader than to endure the consequences of endless battle. T-cell “exhaustion/dysfunction” is thought to help with this, as the loss of T-cell effector functions limits their capacity to inflict damage. Why then even keep such exhausted T cells around? One thought is that they still help contain persistent viruses to subclinical levels without reaching a sterile cure [1, 2]. Another possible reason is proposed by Bae et al. [3].

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References

  1. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol. 2019;37:457–95.

    Article  PubMed  Google Scholar 

  2. Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, et al. Defining ‘T-cell exhaustion’. Nat Rev Immunol. 2019;19:665–74.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bae SP, Kim CY, Lee C-R, Lee C, Payumo RM, Kim SY, et al. Notch2−expressing CD4+ T cells perform immunoregulatory functions during autoimmune inflam mation. Cell Mol Immunol. 2025;22:1077–92.

  4. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T Cells and Human Disease. Annu Rev Immunol. 2020;38:541–66.

    Article  PubMed  Google Scholar 

  5. Milovanovic J, Arsenijevic A, Stojanovic B, Kanjevac T, Arsenijevic D, Radosavljevic G, et al. Interleukin-17 in Chronic Inflammatory Neurological Diseases. Front Immunol. 2020;11:947.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12:49–62.

    Article  PubMed  Google Scholar 

  7. Salomon BL. Insights into the biology and therapeutic implications of TNF and regulatory T cells. Nat Rev Rheumatol. 2021;17:487–504.

    Article  PubMed  Google Scholar 

  8. Fresegna D, Bullitta S, Musella A, Rizzo FR, De Vito F, Guadalupi L, et al. Re-Examining the Role of TNF in MS Pathogenesis and Therapy. Cells. 2020;9:2290.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Saggau C, Bacher P, Esser D, Rasa M, Meise S, Mohr N, et al. Autoantigen-specific CD4(+) T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases. Immunity. 2024;57:2416–32 e8.

    Article  PubMed  Google Scholar 

  10. Balanca CC, Salvioni A, Scarlata CM, Michelas M, Martinez-Gomez C, Gomez-Roca C, et al. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells. JCI Insight. 2021;6:e142513.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, et al. Molecular and transcriptional basis of CD4(+) T-cell dysfunction during chronic infection. Immunity. 2014;40:289–302.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

DA is supported by the Koningin Wilhelmina Foundation for Cancer Research (grants 15330 and 15996) and the Landsteiner Foundation for Blood Cell Research (grant 2125) and a contribution to the Sanquin Research Fund by Abbott Laboratories.

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  1. Sanquin Landsteiner Laboratory for Blood Cell Research, Amsterdam, The Netherlands

    Derk Amsen

  2. Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam, The Netherlands

    Derk Amsen

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Amsen, D. Restoration of the peace in autoimmune disease: tired of fighting?. Cell Mol Immunol 22, 1276–1278 (2025). https://doi.org/10.1038/s41423-025-01335-1

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