Disturbed T Cell Signaling and Altered Th17 and Regulatory T Cell Subsets in the Pathogenesis of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Circulating immune complexes of chromatin and autoantibodies deposit in various tissues leading to inflammation and tissue damage. It has been well documented that autoimmunity in SLE depends on autoreactive T cells. In this review, we summarize the literature that addresses the roles of T cell signaling, and Th17 and regulatory T cells (Tregs) in the development of SLE. T cell receptor (TCR) signaling appears to be aberrant in T cells of patients with SLE. In particular, defects in the TCRζ chain, Syk kinase, and calcium signaling molecules have been associated with SLE, which leads to hyperresponsive autoreactive T cells. Furthermore, in patients with SLE increased numbers of autoreactive Th17 cells have been documented, and Th17 cells appear to be responsible for tissue inflammation and damage. In addition, reduced numbers of Tregs as well as Tregs with an impaired regulatory function have been associated with SLE. The altered balance between the number of Tregs and Th17 cells in SLE may result from changes in the cytokine milieu that favors the development of Th17 cells over Tregs.

Keywords: T cells; TCR signaling; Th17 cells; Tregs; autoimmunity; systemic lupus erythematosus.

Figure 1

Schematic representation of TCR-signaling pathways and aberrancies in SLE. Engagement of TCR, through the recognition of antigen in the context of MHC class II, triggers the assembly of TCR, CD3, and TCRζ chains. TCRζ is phosphorylated and recruits ZAP-70, which in turn phosphorylates LAT. LAT serves as docking protein and phosphorylation initiates the activation of Ras–Erk, calcium-dependent, and PKC-driven signaling pathways. All signals result in the activation of transcription factors, accumulating in the nucleus and influencing gene expression. ^#Signaling components described to be aberrantly regulated in SLE (see Table 1 and text). Therapeutic targets are depicted in red. Key: R788 is Syk inhibitor; KN-93 is CAMK IV inhibitor.

Figure 2

Disturbed balance between Tregs and Th17 cells in SLE. Cytokines important in the induction and proliferation of respective cell types are depicted. Furthermore, also characteristic surface marker, transcription factors, and produced cytokines are illustrated. Red arrows indicate changes in expression found in SLE patients. Furthermore, treatment possibilities are depicted in red.