Ontogeny, Function and Regulation of Follicular T Cells

Abstract

Antibody-mediated immunity plays important roles in effective adaptive immune responses against invading pathogens and its dysregulation could lead to detrimental autoimmune diseases. Follicular helper T (TFH) cells and follicular regulatory T (TFR) cells are specialized CD4 T cells that shape such antibody responses in the germinal centers of secondary lymphoid organs. Here, we utilized single-cell RNA-seq technology to explore the underlying TFH/TFR cell biology regarding their ontogeny, function and regulation. First, we identified a novel TFR cell effector molecule, Fgl2, which directly regulates TFH cells and B cells in a context-dependent and type 2 antibody isotype-specific manner. Fgl2 induces Prdm1 in TFH cells, along with a panel of co-inhibitory molecules and its deficiency resulted in defective antigen-specific immune responses and spontaneous development of Lupus-like autoimmunity associated with elevated autoantibodies. Second, through single-cell RNA-seq analysis, we found the presence of Th1-like TFH cells in our immunization settings and, using T-bet fate reporter mice, demonstrated the existence of linear differentiation trajectory in which Th1 cells could differentiate into Th1-like TFH cells. We also verified the role of STAT3 in such differentiation pathway as its genetic deletion resulted in near complete absence of Th1-like, TFH cells that previously express T-bet. Taken together, we not only identified, characterized and verified a novel TFR effector factor that limit antibody responses and humoral autoimmunity but also revealed ontogenic nature of Th1-like TFH cells. Such findings implicate new potential therapeutic targets that could possibly be intervened in order to improve appropriate humoral effector responses in the context of vaccine development, as well as to better suppress autoreactive reactions in the context of autoimmune diseases.