Citation

IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFN?-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo were poorly understood. The results presented in chapter two of this thesis describe a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(- )CCR2(+)) of GM-CSF/IFN?-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, this work describes an IL23/IL-1/IFN?/TNF?/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFN?-producing Th17 cell formation in vivo. Thus, these results identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFN?-producing Th17 cells. Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells by mechanisms that remain poorly understood. Here, the results presented in chapter three of this thesis identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Further, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. These results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.