PD-1 immunobiology in systemic lupus erythematosus

Abstract

Programmed death (PD)-1 receptors and their ligands have been identified in the pathogenesis and development of systemic lupus erythematosus (SLE). Two key pathways, toll-like receptor and type I interferon, are significant to SLE pathogenesis and modulate the expression of PD-1 and the ligands (PD-L1, PD-L2) through activation of NF-κB and/or STAT1. These cell signals are regulated by tyrosine kinase (Tyro, Axl, Mer) receptors (TAMs) that are aberrantly activated in SLE. STAT1 and NF-κB also exhibit crosstalk with the aryl hydrocarbon receptor (AHR). Ligands to AHR are identified in SLE etiology and pathogenesis. These ligands also regulate the activity of the Epstein-Barr virus (EBV), which is an identified factor in SLE and PD-1 immunobiology. AHR is important in the maintenance of immune tolerance and the development of distinct immune subsets, highlighting a potential role of AHR in PD-1 immunobiology. Understanding the functions of AHR ligands as well as AHR crosstalk with STAT1, NF-κB, and EBV may provide insight into disease development, the PD-1 axis and immunotherapies that target PD-1 and its ligand, PD-L1.

Keywords: Aryl hydrocarbon receptor; Epstein-Barr virus; PD-1; Systemic lupus erythematosus.

Fig. 1.. Common SLE cell signals that modulate the PD-1 axis.

PD-1 receptors are activated by TLR- and Type I IFN-induced NF-κB and/or STAT1 activation. TLR and Type I IFN cell signals are regulated by TAM receptor activity and the functions of suppressor of cytokine signaling (SOCS) and Twist transcriptional repressors. AHR is activated by ligands involved in the etiology, pathogenesis, and treatment of SLE. AHR also exhibits crosstalk with NF-κB and STAT1.

Fig. 2.. Molecules dysregulated in SLE.

(1) Mutations in DNase I can limit the degradation of DNA from apoptotic cells and/or from neutrophil extracellular traps (NETs) and induce the release of nucleic acids that can act as TLR ligands. (2) IFN-α and IDO production are elevated in SLE. TLR ligands induce the production of IFN-α and IDO from antigen presenting cells and endothelial cells. IFN-α also induces the production of IDO and cell surface expression of Axl. (3) TLRs can generate matrix metalloproteinases (MMPs) that cleave Axl from the cell surface. In SLE, soluble Axl (sAxl) is elevated and generated mainly from macrophages and B cells. (4) The production of complement proteins is modulated by TLR ligands. (5) C1q binds antibodies that opsonize the apoptotic cell. C reactive protein (CRP) binds to C1q in activating the complement cascade involving C3b deposition which binds to macrophage complement receptor 1 (CR1). Reduced levels of C1q alter macrophage uptake of apoptotic cells. (6) IDO generates kynurenine from tryptophan that can enhance the formation of Tregs. Kynurenine production is elevated in SLE but the levels of Tregs do not increase. Ligation of Treg Axl with Gas6 enhances their suppressor activity which may be blocked by sAxl. (7) Gas6 sourced from activated endothelial cells is elevated in SLE and binds apoptotic cells and Axl. In SLE, the levels of sAxl may block immune cell recognition of apoptotic cells and alter the function of immune and non-immune cells in the microenvironment.

Fig. 3.. Possible cell signals in lymphocytes.

(1) Distinct endogenous and exogenous AHR ligands regulate the differentiation of lymphocytes. (2) Latent EBV protein EBNA-2 and CD40 ligation induce cell surface expression of CD21. (3) Latent EBV proteins LMP1 and LMP2a mimic respective cell signals induced by CD40 and the BCR. (4) Latent EBV protein EBNA-3 enhances dioxin-induced AHR transcriptional activity. (5) Dioxin-induced AHR activates EBV protein BZLF1 involved in lytic replication and antagonizing NF-κB. (6) LMP1 induces the production of APRIL and the NF-kB-induced expression of PD-L1 and production of BAFF and EBI3. Autocrine APRIL and BAFF activate NF-κB. (7) Axl, activated by Gas6, can complex with kinases (LYN, SYK), activate the PI3K/AKT pathway, or in the presence of type I IFN, activate JAK/STAT signals. In SLE, soluble Axl (sAxl) is produced. (8) CD21 is an EBV receptor that also assists the BCR in the recognition of complement (C3dg, iC3b) bound to antigens. (9) BCR activation induces NF-κB cell signals, CD21 shedding, and the expression of PD-1. (10) B cell PD-1 ligation to PD-L1 inhibits SYK activity. (11) The immunological synapse involves CD40 and B7 ligation associated with MHC:peptide interaction with the TCR for full activation of the B and T cell. (12) LMP1 and TLR NF-κB -induced production of type I IFN activates STAT1. (13) The functions of EBV in T cells are not clearly known. (14) Distinct cytokines regulate the development of T cell subsets. (15) AHR regulates the activity of NF-κB and STAT1 in lymphocytes. (16) In Th17 cells, PD-1 and PD-L1 are repressed whereas in Tregs, these receptors are expressed. T cell PD-1 ligation inhibits activation sequences contained in the immunological synapse. (17) T cell PD-L1 ligation with the B7 molecule, CD80, also suppresses T cell activation. (18) STAT1 antagonizes RORγt which is a transcription factor required for Th17 cell differentiation. Foxp3 and c-Maf are associated with subsets of Tregs. AHR induces the expression of Foxp3 and c-Maf exhibits crosstalk with AHR.