CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL-22

Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22(+)CD4(+) T cells compared with healthy controls resulting in a heightened CD4(+) IFNγ(+)/IL-22(+) ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFNγ) production were elevated within a CD4(+) T-cell subset with phenotypic markers characteristic of naïve T cells (CD3(+)CD4(+)CD27(+)CD45RA(+)CCR7(+)CD95(−)IL-2Rβ(−)) from PsA patients with the highest IFNγ(+)/IL-22(+) ratio of all the CD4 subsets. These unconventional “naïve” CD4(+) T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFNγ production from these unconventional “naïve” T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22(+) T cells overall. Furthermore, blockade of IL-22 enhanced the IFNγ mediated release of CXCL-9. These results reveal CD4(+) T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production.