Regulatory T Cell Dysfunction in Autoimmune Diseases

Abstract

Regulatory T cells (Tregs), a suppressive subpopulation of T cells, are potent mediators of peripheral tolerance, responsible for immune homeostasis. Many autoimmune diseases exhibit disruptions in Treg function or quantity, resulting in an imbalance between protective and pathogenic immune cells. Selective expansion or manipulation of Tregs is a promising therapeutic approach for autoimmune diseases. However, the extensive diversity of Treg subpopulations and the multiple approaches used for Treg identification leads to high complexity, making it difficult to develop a successful treatment capable of modulating Tregs. In this review, we describe the suppressive mechanisms, subpopulations, classification, and identification methodology for Tregs, and their role in the pathogenesis of autoimmune diseases.

Keywords: autoimmune disease; immunology; regulatory T cell.

Figure 1

Suppressive function of regulatory T cells (Tregs). Tregs can exert suppression on various cell types through both direct and indirect mechanisms. Tregs have been observed to have a direct effect on dendritic cells (DCs) via both cytotoxic T lymphocyte antigen-4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3). CTLA-4 and LAG-3 can interact with cluster differentiation 80/86 (CD80/86) costimulatory molecules and major histocompatibility complex (MHC) class II on DCs, respectively. As a result, indoleamine 2,3-dioxygenase (IDO) is generated, which in turn breaks down the essential amino acid tryptophan into kynurenine and inhibits the function and maturation of DCs as they become unable to activate T effector cells (Teffs). Treg cells can interfere with metabolic functions through the expression of ectoenzymes CD39/73, facilitating the generation adenosine. This immunoregulatory purine can then bind to adenosine receptor 2A (A2AR) present on Teff cells and reduce their proliferation. By high expression of CD25, Tregs can sequester interleukin (IL)-2 from the microenvironment, reducing Teff proliferation. Tregs have also been found to express elevated intracellular cyclic adenosine monophosphate (cAMP) levels. Through gap junctions they transfer this to Teffs, which leads to the upregulation of inducible cAMP early repressor (ICER), leading to inhibition of IL-2 transcription and consequently apoptosis due to IL-2 deprivation (indicated by red ‘X’). The release of perforin and granzymes causes damage to the target cell membrane, ultimately inducing apoptosis. Additionally, the secretion of anti-inflammatory cytokines, including IL-10, IL-35, and transforming growth factor-β (TGF-β), restrains the immune responses of T helper (Th)1 and Th17 cells and the production of interferon γ (IFN-γ) and IL-17, respectively. Lastly, Tregs have also been found to directly impact B cells through the interaction of programmed death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1). Abbreviations: ADP: adenosine diphosphate; APC: antigen presenting cell; AMP: adenosine monophosphate; ATP: adenosine triphosphate; A2AR: adenosine receptor 2A; cAMP: cyclic adenosine monophosphate; CD: cluster differentiation; CTLA-4: cytotoxic T lymphocyte antigen-4; DC: dendritic cell; ICER: inducible cAMP early repressor; IDO: indoleamine 2,3-dioxygenase; IL: interleukin; IFN: interferon; LAG3: lymphocyte-activation gene 3; MHC: major histocompatibility complex; NK: natural killer cells; PD-1: programmed death protein 1; PD-L: programmed cell death ligand; Teff: effector T cell; TGF-β: transforming growth factor-β; Treg: regulatory T cell.

Figure 2

Schematic diagram of Treg development. During the rearrangement of the T cell receptor (TCR), thymocytes go through two stages known as positive and negative selection. During positive selection, double positive (DP) T cells receive a survival signal when they bind with sufficient affinity to cortical thymic epithelial cells (cTECs) expressing class I or class II MHC molecules along with self-peptides. Negative selection occurs in the medulla when the TCR of a thymocyte binds with high affinity to a peptide-MHC ligand on medullary thymic epithelial cells (mTECs), resulting in a self-reactive CD4+ single positive (SP) T cell and subsequent apoptotic cell death. As this process is not always effective, some self-reactive T cells evade elimination and enter the periphery, possibly causing autoimmune diseases. High-affinity tissue-restricted binding of MHC II/TCR and subsequently IL-2 or IL-15 signaling result in nTreg development by upregulation of FoxP3 and CD25. Low-affinity binding results in naïve CD4+ T cells. These naïve CD4+ T cells may develop in the periphery to iTregs in response to environmental factors such as commensal microbiota, allergens, food antigens, IL-2, and TGF-β. In the periphery, Tregs play a role in suppressing immune responses directed against both self and non-self-antigens. This involves the secretion of inhibitory cytokines (IL-10, IL-35, and transforming growth factor-β (TGF-β)), inhibition of effector cells through granzyme-dependent and IL-2 cytokine-deprivation mediated mechanisms, and modification of DC function and maturation through cell-contact-dependent interactions. Abbreviations: CD: cluster differentiation; cTEC: cortical thymic epithelial cells; DP: double positive (CD4+CD8+); IL: interleukin; iTreg: induced Treg; MHC: major histocompatibility complex; mTEC, medullary thymic epithelial cells; nTreg; natural Treg; SP: single positive (CD4+ or CD8+); TCR: T cell receptor; Teff: effector T cell; TGF-β: transforming growth factor-β; Treg: regulatory T cell.

Figure 3

New therapeutic approaches for autoimmune diseases, encompassing both cell-based and non-cell-based strategies. Cell-based therapies involve the use of ex vivo expanded polyclonal Tregs or Tregs modified with autoantigen-specific T cell receptors (TCRs), chimeric antigen receptors (CARs), or another chimeric receptor-like peptide-MHC. Another cell-based approach focuses on harnessing the immunomodulatory effects of tolerogenic dendritic cells (DCs). Additionally, fecal transplantation of Treg-promoting bacteria shows promise in restoring immune balance. Non-cell-based therapies encompass biologicals such as low-dose IL-2 therapy, TNFR2 agonist therapy, and an anti-CD20 antibody rituximab. Pharmacological agents such as rapamycin can also enhance Treg proliferation. Furthermore, the administration of autoantigens through various methods enables vaccination against autoimmune responses. Finally, combining these therapies has the potential to yield greater efficacy compared to single interventions. Adapted from [150] “Treg Enhancing Therapies to Treat Autoimmune Diseases” by P. Eggenhuizen, B. H. Ng, and J. D. Ooi, 2020, 21p, 7015, International Journal of Molecular Sciences. Abbreviations: CD: cluster differentiation; CAR: chimeric antigen receptor; DC: dendritic cells; IL-2: interleukin 2; Tconv: conventional T cell; TCR: T cell receptor; TNFR2: tumor necrosis factor receptor 2.