It is widely accepted that effector Th cells have inflammatory capabilities. Th22 cells are CD4+
effector Th cells that produce IL-22 and TNF-α. They are a unique subset of Th cells that develop along a pathway distinct from the Th1-, Th2-, and Th17-differentiation pathways (10
). IL-22 is an inflammatory cytokine that promotes inflammatory responses and correlates with autoimmune disorders (12
). In addition, Th22 cells play an important role in the pathogenesis of experimental autoimmune disease models (26
IL-22 secreted by Th22 cells primarily affects epithelial and stromal cells rather than other hematopoietic cells, which lack a functional IL-22R. Expression of the CCR4 and CCR10 skin-homing receptors on Th22 cells suggests that they are likely to be recruited to the skin, where they may contribute to host defense against microbial pathogens and promote tissue repair or remodeling. Multiple studies indicate that Th22 cells may also be involved in the pathogenesis of inflammatory skin disorders, such as psoriasis, atopic eczema, and allergic contact dermatitis (10
). Although several investigators reported that Th22 cells are involved in the pathogenesis of inflammatory skin disorders, to the best of our knowledge there have been no reports of a relationship between Th22 cells and Behçet’s disease. Therefore, we designed experiments to determine whether Th22 cells are involved in the pathogenesis of uveitis in Behçet’s disease.
In the current study, we showed that Th22-type TCCs established from ocular samples from patients with active uveitis, including those with Behçet’s disease, produced large amounts of the Th22-associated cytokines IL-22 and TNF-α but not Th1/Th17 cytokines. In addition, CD4+ T cell lines from PBMCs produced large amounts of IL-22, as well as other inflammatory cytokines, suggesting that Behçet’s disease T cells established from inflamed eyes and peripheral blood cells may include Th22-type effector cells. Additionally, fresh CD4+ T cells from patients with active uveitis and Behçet’s disease, without systemic treatment, highly expressed IL-22, TNF-α, and CCR10. We also demonstrated that Th22 cells exposed to infliximab in vitro failed to produce IL-22 and TNF-α, suggesting that TNF-α is required for Th22 differentiation in Behçet’s disease. To confirm this result, we used both human and mouse rTNF-α proteins. CD4+ Behçet’s disease T cells exposed to TNF-α in vitro produced IL-22, and murine Th1 and Th17 cells produced large amounts of IL-22 when cultured with mouse rTNF-α.
In addition, fresh T cells from a uveitis patient with Behçet’s disease expressed high levels of Th22-related molecules, such as IL-22, TNF-α, and CCR10, whereas fresh T cells from a Behçet’s disease patient being treated with infliximab expressed low levels of these molecules. Similarly, Th22 clones from Behçet’s disease uveitis patients expressed high levels of Th22-related molecules, but the expression was suppressed in Th22 cells cultured with infliximab. Importantly, the expression of Th22-related molecules was greatly suppressed in Th22 cells cultured with both anti–TNF-α and anti–IL-6 blockades. These results suggest that these blockades may prevent the differentiation of Th22 cells. In fact, infliximab successfully controls inflammation in the eyes of patients with Behçet’s disease (17
). Thus, suppression of effector T cell differentiation by anti–TNF-α therapy may protect uveitis patients from severe ocular inflammation.
Fresh intraocular T cells from mice with EAU contained a large population of IL-22+ cells, suggesting that CD4+ IL-22+ Th22-type T cells may be associated with the pathogenic mechanisms of intraocular inflammation. We also showed that retinal Ag-specific CD4+ T cells from EAU mice produced large amounts of IL-22 in the presence of retinal Ags (IRBP peptides). Additionally, we showed that anti-mouse IL-22–blocking Abs, together with anti-mouse TNF-α Ab, greatly suppressed intraocular inflammation in EAU models (see ).
IL-22 is an inflammatory cytokine that promotes inflammatory responses and correlates with autoimmune disorders, such as rheumatoid arthritis (25
), Crohn’s disease (26
), and skin inflammatory diseases (11
). In a mouse model of psoriasis, dermal inflammation is suppressed in IL-22–deficient mice (27
T cells and IL-22 contribute to the inflammatory response and promote epithelial healing, including the corneal epithelium (30
). However, the role of IL-22/Th22 cells in inflammation remains controversial. We found that the production of inflammatory chemokines by T cells is enhanced by exposure to supernatants from Behçet’s disease Th22 cells. T cells exposed to Th22 supernatants expressed high levels of mRNA for chemokines, suggesting that Th22-type cytokines and cells may be involved in the acute immune response in Behçet’s disease. Although the proinflammatory responses are synergistically dependent on IL-22 and TNF-α (12
), Behçet’s disease T cells, such as intraocular-infiltrating cells, include Th22 cells, and the T cells produce large amounts of both IL-22 and TNF-α.
In conclusion, the inflammatory cytokine IL-22 seems to enhance the inflammatory response in Behçet’s disease patients who have uveitis. The proinflammatory cytokine TNF-α may promote Th22 differentiation in Behçet’s disease. Thus, Th22 cells that produce IL-22 and TNF-α constitute a novel subset of effector Th cells in Behçet’s disease. We are now conducting experiments to determine whether IL-22/Th22 cells are involved in the pathogenesis of inflammation in other types of uveitis (noninfectious and infectious), and we are also investigating whether ocular-resident tissues, such as retinal pigment epithelium, can suppress these effector T cells in vitro.