Figure 1.

Th17 pathogenesis via T-cell receptor (TCR) stimulation, cytokine signaling, and Ca²⁺ signaling. Antigen stimulation of the TCR complex via MHC class II interactions triggers downstream signaling pathways through activation of TCR-associated scaffolding/adaptor proteins. Phosphorylation of the TCR ζ chain by lymphocyte-specific protein tyrosine kinase (LCK) recruits ZAP70 to the TCR complex. LAT and SLP-76 are subsequently phosphorylated by ZAP70, resulting in assembly and activation of Vav1 and PLC-γ1. Phosphorylated PLC-γ1 hydrolyzes membrane-bound PIP2 into DAG and IP3 and results in the binding of IP3 to the endoplasmic reticulum (ER)–bound IP3 receptor (IP3R). Depletion of ER stores, which occurs following InsP3R-mediated ER Ca⁺ efflux, is detected by STIM proteins on the ER membrane. Upon sensing Ca²⁺ depletion, STIM oligomerizes and moves to the ER–plasma membrane (PM) junction, where it engages Orai1 to activate CRAC channels. Sustained Ca²⁺ entry via CRAC channels raises cytoplasmic calcium levels and allows for activation of calcineurin, which induces nuclear factor of activated T-cell (NFAT) dephosphorylation and translocation to the nucleus. At the same time, key cytokines produced within the local inflammatory environment bind to corresponding cytokine receptors along the cell membrane. Interleukin (IL) 6, IL-23, IL-21, and IL-1β signaling converge to induce STAT3-mediated transcription. Together, NFAT and STAT3 help induce expression of characteristic “homeostatic” Th17 molecular markers (RORγt, IL-17A, IL-17F, IL-21, and IL-22), which may subsequently transition to a distinct pathogenic profile involving expression of T-bet (aka T-box transcription factor TBX21), interferon-γ (INF-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The precise mechanism connecting SOCE, cytokine signals, and the conversion to this pathogenic lineage of Th17 cells remains to be fully elucidated. Modified from Srikanth et al. (2017).