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Review
. 2022 Sep 29;79(10):533.
doi: 10.1007/s00018-022-04563-0.

Regulatory T cells in rheumatoid arthritis: functions, development, regulation, and therapeutic potential

Shuaifeng Yan #  1   2 , Konstantin Kotschenreuther #  1 , Shuya Deng  3 , David M Kofler  4   5
Affiliations
Review

Regulatory T cells in rheumatoid arthritis: functions, development, regulation, and therapeutic potential

Shuaifeng Yan et al. Cell Mol Life Sci. .

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that mainly affects the joints but also leads to systemic inflammation. Auto-reactivity and dysregulation of self-tolerance are thought to play a vital role in disease onset. In the pathogenesis of autoimmune diseases, disturbed immunosuppressive properties of regulatory T cells contribute to the dysregulation of immune homeostasis. In RA patients, the functions of Treg cells and their frequency are reduced. Therefore, focusing on the re-establishment of self-tolerance by increasing Treg cell frequencies and preventing a loss of function is a promising strategy for the treatment of RA. This approach could be especially beneficial for those patients who do not respond well to current therapies. In this review, we summarize and discuss the current knowledge about the function, differentiation and regulation of Treg cells in RA patients and in animal models of autoimmune arthritis. In addition, we highlight the therapeutic potential as well as the challenges of Treg cell targeting treatment strategies.

Keywords: Autoimmunity; CD4+ T cells; Chimeric antigen receptor; Regulatory T cells; Self-tolerance; Therapeutic potential.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The mechanisms of immunosuppressive function mediated by Treg cells. Treg cells secret the cytokines TGF-beta, IL-10 and IL-35 to directly inhibit the activation and proliferation of effector T cells. CTLA-4, LAG-3 and PD1 on Treg cells mediate the downregulation of APC cell functions, which prevents the activation of naïve T cells and effector T cells. CD25 expressed on Treg cells outcompetes IL-2 which is necessary for T cell in the peripheral to prevent its activation and proliferation. Adenosine produced by the hydrolyzation of CD39 and CD73 from ATP or ADP binds to A2A receptor on effector T cells, thereby inhibiting the proliferation and production of inflammatory cytokines. Treg cells also mediate the cytolysis of effector T cells by granzymes and perforin
Fig. 2
Fig. 2
Strategies to increase Treg cells frequencies and the suppressive function in vivo and in vitro. In vivo and in vitro strategies can be used to increase Treg cells number or function with immunomodulatory drugs. Low dose IL-2, engineered IL-2 muteins, the complex of IL-2/IL-2 receptor, IL-4, IL-5, IL-7, IL-12, IL-15, and IFN-γ are shown to have the potential to increase the activity of natural Treg cells or peripheral Treg cells against effector T cells in vivo. In addition, selective depletion of effector T cells by anti-CD3 antibodies can restore Treg cell predominance over effector T cells. Treg cells or naïve T cells isolated from the peripheral blood or the thymus of pediatric cardiac patients can be expanded and genetically modified in vitro for adaptive transfer to increase Treg cell numbers or improve specificity
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