IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells

Abstract

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.

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.…”

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…In brief, polarized whole spleen cells were further stimulated for 5 h with PMA/ionomycin/BFA (20 ng/mL PMA, 1 lg/mL ionomycin, 5 lg/mL BFA) at 37 C. Cells were stained with surface markers anti-CD4-PeCy7 (RM4-5), and then with intracellular cytokine anti-IL-17-PE mAb (TC11-18H10.1) (BD Bioscience). Results were analyzed by flow cytometry [9,44].…”

Interleukin‐21 administration to aged mice rejuvenates their peripheral T‐cell pool by triggering de novo thymopoiesis

“…S4). These qPCR results are consistent with the observed decrease in IFNγ ( T‐bet ) and IL‐17 ( RORC ) secretion levels and are particularly interesting as several investigations have associated IL‐21 to autoimmune diseases (Korn et al ., 2007; Peluso et al ., 2007; Attridge et al ., 2012). Further analyses conducted on rIL‐21‐treated aged mice showed no unusual signs of inflammation or autoimmunity (Fig.…”