Regulatory T cells in acute and chronic kidney diseases

Abstract

Foxp3-expressing CD4⁺ regulatory T cells (Tregs) make up one subset of the helper T cells (Th) and are one of the major mechanisms of peripheral tolerance. Tregs prevent abnormal activation of the immune system throughout the lifespan, thus protecting from autoimmune and inflammatory diseases. Recent studies have elucidated the role of Tregs beyond autoimmunity. Tregs play important functions in controlling not only innate and adaptive immune cell activation, but also regulate nonimmune cell function during insults and injury. Inflammation contributes to a multitude of acute and chronic diseases affecting the kidneys. This review examines the role of Tregs in pathogenesis of renal inflammatory diseases and explores the approaches for enhancing Tregs for prevention and therapy of renal inflammation.

Keywords: AKI; IRI; Tregs; cytokine; inflammation; nephrotoxicity.

Fig. 1.

Regulators and regulatory mechanisms of Tregs. The CD4⁺Foxp3⁺ Tregs are primarily defined by the expression of Foxp3 transcription factor and high-affinity IL-2 receptor (IL-2Rα or CD25). The most important factors for thymic Tregs, which also express Helios transcription factor, include TCR/CD28 signaling and IL-2. In addition, several other mechanisms are utilized for the differentiation, maintenance, and functions of Tregs. TGF-β, which is one of the suppression mechanisms used by Tregs, along with IL-2, converts naïve T cells to Tregs during T-cell receptor (TCR) stimulation. IL-33 is the newest factor that can promote differentiation, proliferation, and function of Tregs. Other major mechanisms are highlighted. Tregs can suppress target cells through IL-2 consumption, adenosine, soluble mediators, costimulatory molecules, and direct cytotoxicity. Trafficking and adhesion molecules also play important roles in Treg function. Costimulatory molecules: CD28; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; GARP’, glycoprotein A repetitions predominant; GITR, glucocorticoid-induced tumor necrosis factor-related receptor; PD-1, programmed death 1. Cytokines: IL-2, interleukin-2; tripartite IL-2 receptor IL-2Rα, CD25, IL-2Rβ, and IL-2Rγ; ST2, IL-33 receptor; interleukin (IL)-2 receptor α chain IL-33, interleukin-33; 2A_2AR; TGF-β, transforming growth factor-β; TGF-βR, TGFβ receptor. Soluble mediators of suppression: IL-10, interleukin-10; IL-35, interleukin-35. Cytotoxicity: granzyme B; FasL, Fas ligand. Adhesion molecules: ItgαVβ8, integrin αVβ8 (also involved in TGF-β activation); CD103, integrin αE; Nrp1, neuropilin-1. Adenosine metabolism: CD39 and CD73, ectonucleotidases; A2A adenosine receptor.

Fig. 2.

Transcriptional regulation of Foxp3. Foxp3 transcription is controlled by binding of a diverse set of transcription factors to distinct regulatory elements in the Foxp3 gene, namely promoter, conserved noncoding sequence (CNS) 1, CNS2, and CNS3. Regulators downstream to TCR/CD28 signaling bind at all the elements. IL-2 signaling recruits activated STAT5 to the promoter and CNS2, while TGF-β-mediated Smad and other peripheral (induced) Tregs related transcriptional factors (RAR, Foxo) bind to CNS1. Foxp3 is an autoregulator and binds to CNS2 as a trinary complex with Cbf-β and RUNX1. Demethylation of CpG islands in CNS2 regulate tTreg stability, and CNS1 may regulate iTreg differentiation, whereas CNS3 may regulate precursors to Tregs. The upstream signals and transcription factors are color coded. Upstream pathways inducing expression of the downstream transcription factors are depicted in the same color. AP1, activator protein 1; c-Rel and p65, members of NF-κB transcription factor family; CREB, cyclic-AMP-responsive element-binding protein; NFAT, nuclear factor of activated T cells; STAT5, signal transducer and activator of transcription; ST2, receptor for IL-33; Gata3, GATA binding protein 3, Pol II, RNA polymerase II; SMAD3, mothers against decapentaplegic homolog; Cbf-β, core-binding factor, β subunit; Foxp3, forkhead box P3; RUNX, runt-related transcription factor 1; Nr4a, nuclear receptor 4a; Foxo, forkhead box O; RAR, retinoic acid receptor. [From Huehn and Beyer (84).]

Fig. 3.

Treg-enhancing strategies to protect from renal inflammatory diseases. In addition to the adoptive transfer, several other approaches have been used to promote the number and function of endogenous Tregs. These include small molecules such as fingolimod (FTY720), mycophenolate mofetil (MMF), adenosine receptor (A₂AR) agonists, oxidized ATP (oATP), constituent of bee venom (PLA2); cell transfusions such as mesenchymal stem cells (MSCs), tolerogenic dendritic cells (DC); macromolecules including, rituximab, CD28 superagonists, low-dose IL-2, IL-2/anti-IL-2 complex and the recently described IL233 fusion cytokine, which bears IL-2 and IL-33 activities in one molecule. IL-2 upregulates the ST2 (IL-33 receptor) on Tregs enabling IL-2 and IL-33 to synergize and promote activation, proliferation, and recruitment of Tregs to protect from renal inflammatory diseases induced by ischemia-reperfusion, nephrotoxicity, lupus nephritis, and diabetic nephropathy, all of which contribute to end-stage renal disease (ESRD). Please see the text for details.