From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited

Abstract

Protracted inflammation leading to dysregulation of effector T-cell responses represents a common feature of a wide range of autoimmune diseases. The interleukin-12 (IL-12)/T-helper 1 (Th1) pathway was thought to be responsible for the pathogenesis of multiple chronic inflammatory diseases, including psoriasis, inflammatory bowel disease, arthritis, or multiple sclerosis, mainly through their production of interferon-gamma and its effects on macrophage activation and chemokine production. However, this initial concept of T-cell-mediated chronic inflammation required an adjustment with the discovery of an IL-12-related cytokine, designated IL-23. IL-23 was rapidly recognized for its involvement in the establishment of chronic inflammation and in the development of a Th cell subset producing IL-17, designated Th17, which is distinct from the previously reported Th1 and Th2 populations. This review aims to describe the characterization of IL-23 and its receptor, its biological activities, as well as its involvement in the development of human Th17 cells and autoimmunity.

Fig. 1. Overview of IL-12 and IL-23 ligand and receptor complexes

Fig. 2. IL-23 induces polarization of naive CD4⁺ T cells

Naive CD4⁺ T cells were isolated from cord blood, primed for 6 days, and recultured for an additional 6 days in the presence of the indicated cytokines, anti-CD3, IL-2, and irradiated CD32/CD58/CD80-transfected L cells. Cells were harvested at day 6 (left) and day 12 (right) and stimulated for 24 h.

Fig. 3. IL-23 induces polarization of naive CD4⁺ T cells

Naive CD4⁺ T cells were isolated from cord blood, primed for 6 days, and recultured for an additional 6 days in the presence of the indicated cytokines, anti-CD3, IL-2 and irradiated CD32/CD58/CD80-transfected L cells. Cells were harvested at days 6 and 12 and stimulated for 6 h.

Fig. 4. IL-23-induced polarization is inhibited by neutralizing antibodies against p40 and IL-12Rβ1 but not p35

Fig. 5. Th17 cell differentiation in mouse and human

Fig. 6. IL-23/Th17 pathway and inflammation

In response to inflammatory stimuli, dendritic cells produce IL-23 and IL-1β, which induce development of Th17 cells that produce IL-17, IL-22, IL-17F, and other proinflammatory cytokines. This inflammatory milieu, through its action on epithelial cells, will contribute to epithelial barrier disruption and recruitment of immune cells.