Induction and interactions of γδ T cell and Th17 cell signaling pathways in MS and EAE. In the induction phase, pathogen-associated molecular patterns (PAMP) from commensal bacteria and danger-associated molecular patterns (DAMP) from dead/dying cells bind to pattern recognition receptors (PRR) on monocytes and dendritic cells (DC). Activated DC and monocytes secrete interleukin (IL)-β, IL-23, and IL-6. IL-β and IL-23 activate γδ T cells leading to IL-17, IL-21, and granulocyte-macrophage colony stimulating factor (GM-CSF) production. Activated DC present antigenic peptide by MHC class II molecules to T cell receptors (TCR) on Tnaive (CD4) T cells. Antigenic peptide presentation along with co-stimulatory signals from DC (IL1-β, IL-6 and IL-23) activates Th17 cells that respond and secrete IL-17, GM-CSF, and IL-21. These cytokines are also released from activated γδ T cells and jointly combine to initiate pro-inflammatory feedback loops that augment the production of IL-1β, IL-6, and IL-23 by antigen presenting cells (APC), leading to enhanced Th17 responses and continued γδ T cell activation of the effector phase. IL-17 and IL-21 act in an autocrine manner to enhance IL-17 production by Th17 T cells in the development of EAE. Lastly, activated γδ T cells suppress T regulatory (Treg) responses, promoting the pro-inflammatory profile by effector T cells. Adapted from McGinley et al.