PPP2R2D suppresses IL-2 production and Treg function

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex pathogenesis. The expression of autoimmunity and organ inflammation involves altered production of cytokines by T cells (1-3). Specifically, decreased IL-2 production may account for the reported decreased cytotoxic T cell function and the decreased function and numbers of Tregs (2), whereas increased production of IFN-γ and IL-17 may contribute directly to organ inflammation (4, 5). Treatment with low doses of IL-2 diminishes renal inflammation and the rate of kidney-infiltrating CD4 + T cells in murine lupus nephritis (6). Low-dose IL-2 in the treatment of autoimmune diseases including SLE, rheumatoid arthritis, and multiple sclerosis is in clinical trials (7). IL-2 is a pleiotropic cytokine produced by effector T (T eff) cells after antigen activation and is at the crossroads of effector responses, tolerance, and immunotherapy (8). IL-2 transcription is mediated by multiple transcription factors (TFs), including activator protein-1 (AP-1, FOS-JUN family dimers), cAMP responsive element binding protein (CREB), nuclear factor of activated T cells (NFAT) family proteins, NF-κB, ETS-related TF (Elf1), and GA binding protein α chain (GABPA) (9). Tregs have abundant expression of the IL-2 receptor α chain (CD25) but are unable to produce IL-2. IL-2 binds with low affinity to CD25 or to heterodimers of the common γ chain (CD132) and IL-2Rβ (CD122), but receptor affinity increases about 1000-fold when these subunits collectively interact with IL-2 (10). Capture of IL-2 by Tregs is critical for their suppressor function and for limiting the activation of T cells (11). Protein phosphatase 2A (PP2A) is a ubiquitously expressed and highly conserved serine/threonine phosphatase that is important in multiple cellular processes, including cell division, cytoskeletal dynamics, and various signaling pathways (12). The PP2A core enzyme consists of the scaffold subunit A (PP2A A) and the catalytic subunit C (PP2A C). To form a functional holoenzyme, the core enzyme interacts with one of the many regulatory subunits (PP2A B), which define substrate and tissue specificity (13). The regulatory subunits are classified into 4 major families, identified as B (e.g.

Genetic Variations Controlling Regulatory T Cell Development and Activity in Mouse Models of Lupus-Like Autoimmunity

“…Moreover, HIF-1α directly activates the Ifng promoter. These results contrast with the lack of phenotype resulting from direct deletion of Hif1a in Treg cells ( 59 ), and suggest that HIF-2α constitutive expression in VHL-deficient Treg cells is likely to play a role.…”

“…PPP2R2D is a regulatory subunit of PP2A whose expression is increased in T cells from patients with SLE. Mice with PPP2R2D-deficient T cells developed a reduced systemic autoimmunity in response to TLR7 activation ( 59 ). Furthermore, PPP2R2D-deficiency enhanced the suppressive function of Treg cells, which was supported by an increased IL-2 transcription in conventional T cells, a process that is negatively regulated by PPP2R2D ( 59 ).…”

“…Mice with PPP2R2D-deficient T cells developed a reduced systemic autoimmunity in response to TLR7 activation ( 59 ). Furthermore, PPP2R2D-deficiency enhanced the suppressive function of Treg cells, which was supported by an increased IL-2 transcription in conventional T cells, a process that is negatively regulated by PPP2R2D ( 59 ). Therefore, PPP2R2D regulates Treg cells through PP2A in a cell-extrinsic manner (IL-2 secretion from conventional T cells), as opposed to PP2A controlling Treg function through mTORC1 in a cell-intrinsic manner.…”

Current Insights and Future Prospects for Targeting IL-17 to Treat Patients With Systemic Lupus Erythematosus

“…Recently, our group has shown that PPP2R2D, a regulatory subunit of PP2A, is increased in T cells from SLE patients. Mice lacking this subunit in T cells have less autoimmunity and PPP2R2D negatively regulates IL-2 production in conventional T cells by regulating the chromatin opening of the IL-2 gene ( 43 ).…”

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

“…Th17 cells are characterized by the molecular determinants mir26 [ 110 ], HIF-1, pyruvate kinase M2 (PKM2) [ 111 ] and adiponectin [ 112 ]. Treg cells (Foxp3+) have a suppressive function with respect to autoimmune reactivity [ 113 ]. In addition, these cells, via epigenetic regulatory mechanisms, maintain self-tolerance and support organ homeostasis [ 114 ].…”