Generation of T Follicular Helper Cells Is Mediated by Interleukin-21 but Independent of T Helper 1, 2, or 17 Cell Lineages

Abstract

After activation, CD4+ helper T (TH) cells differentiate into distinct effector lineages. Although CXCR5+ follicular TH (TFH) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that TFH cells have a distinct gene expression profile from other effector T cells and develop in vivo independent of the TH1 or TH2 lineages. TFH cell generation is regulated by B7h expressed on B cells and, similar to TH17 cell development, is dependent on IL-21, IL-6 and STAT3. However, differentiation of TFH cells, unlike TH17 cells, does not require TGFβ signaling or TH17-specific orphan nuclear receptors RORα and RORγ in vivo. Finally, naïve T cells activated in vitro in the presence of IL-21 but not TGFβ signaling preferentially acquire TFH gene expression and function to promote germinal center reactions in vivo. This study thus demonstrates TFH as a distinct lineage of effector TH differentiation.

B Cell–Specific Expression of Inducible Costimulator Ligand Is Necessary for the Induction of Arthritis in Mice

“…Production of the T cell cytokines IFN␥, IL-17, IL-4, IL-10, and IL-21 was significantly inhibited, whereas IL-6 production was not inhibited (Figure 2). cells (17,31). To determine whether resistance to arthritis in ICOSL Ϫ/Ϫ mice is associated with a reduction in the percentage of GCs and PCs, we examined spleen cells from PG/DDA-immunized mice at the time point when WT mice were arthritic.…”

“…In the absence of ICOS (e.g., ICOS Ϫ/Ϫ mice), GC formation is defective, and T cell-dependent antibody responses are impaired (15,16). Specific ablation of ICOSL on B cells leads to reduced numbers of Tfh cells, indicating that Tfh cells are dependent on signaling from B cells (17).…”

Inducible costimulator ligand regulates bleomycin‐induced lung and skin fibrosis in a mouse model independently of the inducible costimulator/inducible costimulator ligand pathway

“…The ICOS/ICOSL pathway promotes T cell activation, differentiation, and effector responses, and T celldependent B cell responses. ICOS-mediated costimulation of T cells leads predominantly to the production of effector cytokines, such as interleukin-4 (IL-4) and IL-10, and to a lesser extent, IL-2, interferon-␥ (IFN␥), and tumor necrosis factor ␣ (TNF␣) (11), thereby playing a more important role in Th2 responses than in Th1 responses (7,(12)(13)(14). Furthermore, recent studies demonstrated that ICOS influences the expansion of follicular T cells, Th17 cells, and regulatory T cells (15)(16)(17).…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Recent studies have implicated novel T helper cell subsets as initiators of ELF formation. Given the role that cytokines play in the regulation of T helper cell differentiation and effector function, a number of cytokines have now been linked with the control of ELF s. For example, cytokines involved in the regulation of T helper type 17 (Th17) cell responses ( IL ‐6, IL ‐21, IL ‐23, IL ‐27, IL ‐2, IL ‐22, IL ‐17)23, 137, 139, 145, 148, 152 and follicular T helper (Tfh) cell responses [ IL ‐6, IL ‐21, Type I interferons ( IFN s), IL ‐27, IL ‐2]137, 139, 146, 147, 150 are emerging as regulators of lymphoid neogenesis. Here we highlight cytokines that may positively (red) and negatively (blue) control ELF s based on their ability to regulate effector T‐cell populations involved in ELF development or function.…”