Foxp3+ Regulatory T Cells of Psoriasis Patients Easily Differentiate into IL-17A-Producing Cells and Are Found in Lesional Skin

Abstract

Psoriasis is an autoimmune-related chronic inflammatory skin disease that is strongly associated with IL-23 and T helper-17 (Th17) effector cytokines. In addition, CD4+CD25(high) regulatory T-cell (Treg) function appeared to be impaired in psoriasis. CD4+CD25(high)Foxp3+ Tregs are typically considered inhibitors of autoimmune responses. However, under proinflammatory conditions, Tregs can differentiate into inflammation-associated Th17 cells--a paradigm shift, with as yet largely unknown consequences for human disease initiation or progression. Th17 cells are highly proinflammatory T cells that are characterized by IL-17A and IL-22 production and expression of the transcription factor retinoic acid-related orphan receptor γt (RORγt). We here show that Tregs of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation. This enhanced Treg differentiation was linked to unexpectedly high RORγt levels and enhanced loss of Foxp3. Notably, IL-23 boosted this Treg differentiation process particularly in patients with psoriasis but less so in controls. IL-23 further reduced Foxp3 expression while leaving the high RORγt levels unaffected. The histone/protein deacetylase inhibitor, Trichostatin-A, prevented Th17 differentiation of Tregs in psoriasis patients. Importantly, IL-17A+/Foxp3+/CD4+ triple-positive cells were present in skin lesions of patients with severe psoriasis. These data stress the clinical relevance of Treg differentiation for the perpetuation of chronic inflammatory disease and may pave novel ways for immunotherapy.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…Changes in epigeneticcontrol mechanisms may allow for switching between exhausted and activated T cell states. In addition, T reg cells can be converted into T H 17 cells in the presence of IL-6 and TGF-β 46,47 , which might underlie certain forms of autoimmunity, such as autoimmune hepatitis and psoriasis 48,49 , and CXCL11 promotes T reg cell differentiation into CXCR3 + CD4 + effector T cells, suggesting that it might be involved in the development of autoimmune encephalitis 50 . Control of T reg cell plasticity is further regulated by EZH2, a target for multiple small-molecule inhibitors in cancer trials 51 .…”

IL-37 Ameliorates the Inflammatory Process in Psoriasis by Suppressing Proinflammatory Cytokine Production

“…The presence of IL-37 in T EM cells may illustrate the possible regulation of IL-37 in T EM cells through the inhibition of Th1 activity, as revealed by our in vivo study. Considerable numbers of Tregs, characterized by high expression of Foxp3 staining, are present in the skin lesions of psoriasis and are supposed to serve as a brake for cutaneous inflammation (56). A recent study (57) demonstrated that the capacity of Tregs to enforce tolerance to harmless and self-Ags is severely ablated by their less intrinsic activity and the proinflammatory cytokine milieu in psoriasis.…”

New insights of T cells in the pathogenesis of psoriasis

“…Based on these findings, Bovenschen et al 96 demonstrated that this subset of Tregs from patients with severe psoriasis were more prone to differentiate into IL-17-producing cells compared to healthy controls upon stimulation. Most importantly, they found that there was a specific population of CD4 1 IL-17A 1 Foxp3 1 cells in the skin lesions, which they assume would probably contribute to the disease development.…”