1. Figure 2 Molecular pathways involved in the regulation of T-cell differentiation and cytokine production
Figure 2 | Molecular pathways involved in the regulation of T-cell differentiation and cytokine production. Many cytokines and chemokines that are upregulated in autoimmune nephritis, such as IL-6, IL-21, IL-23 and transforming growth factor β (TGFβ), cause downstream activation of STAT3 transcriptional targets, including IL-17 and BCL-6, contributing to inflammation and supporting antibody production. In patients with systemic lupus erythematosus, the CD3 complex is rewired in T cells by replacing CD3ζ with the common Fcγ, which results in increased calcium responses, enhancing the activity of calcium/calmodulin-dependent protein kinase IV (CaMKIV) which in turn increases the binding of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) to the IL-17 and IL-2 promoters enhancing and repressing them respectively. In addition, enhanced expression of protein phosphatase 2A (PP2A) suppresses the MAPK–DNMT1 pathway and dephosphorylates cyclic AMP-responsive element-binding protein 1 (CREB), resulting in decreased IL-2 production. PP2A also acts through Rho-associated protein kinase (ROCK) to enhance binding of the IL-17 transcription enhancer interferon regulatory factor 4 (IRF4), and suppresses ELF-1 which is an enhancer of CD3ζ and a repressor of Fcγ. Signalling through CD44 is accentuated by ROCK, which promotes cell migration and binding of IRF4 to the IL-17 promoter. CCR6, C-C chemokine receptor type 6; ERM, ezrin/radixin/moesin protein complex; HA, hyaluronic acid; ICOS, inducible T-cell costimulator; R, receptor; TCR, T cell receptor.
Suárez-Fueyo, A. et al. (2017) T cells and autoimmune kidney disease
Nat. Rev. Nephrol. doi: /nrneph