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L. P. Schewitz, L. B. Nicholson, A. D. Dick, R. W. Lee; CD4+CD25IntCD45RO+ T Cells Are Refractory to Glucocorticoid Treatment and Mediate IL-17 Production. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3595.
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© ARVO (1962-2015); The Authors (2016-present)
Suboptimal responses to corticosteroid therapy represent a major disease burden across medical specialities. We have previously identified a subpopulation of steroid refractory (SR) CD4+ T cells prevalent in patients with both SR uveitis and SR ulcerative colitis, and demonstrated that the SR phenotype is restricted to CD4+ T cells expressing intermediate levels of the -subunit of the IL-2 receptor (CD25int cells). In experimental models of asthma Th17 cells have also been shown to be SR. Therefore, the purpose of this study was to further refine the SR CD4+CD25int cell phenotype, and in particular to evaluate their potential for generating IL-17.
Human PBMCs from 6 healthy volunteers were FACS Vantage sorted into CD4+CD25neg/intCD45RO+/- and cultured with CD3/CD28 beads in the presence of high-dose (10-6M) Dex as previously described. Proliferation was then quantified at day 5 by CFSE dilution. In addition, expression of Th1, Th17 and memory cell markers in each CD4+CD25neg/intCD45RO+/- subset was determined by 9 colour flow-cytometry, both pre-culture and following stimulation with PMA/ionomycin
Inhibition of proliferation by Dex, quantified as percentage suppression relative to positive control cultures, was significantly greater in CD4+CD25intCD45RO-, CD4+CD25negCD45RO+ and CD4+CD25negCD45RO- cells than in CD4+CD25intCD45RO+ cells (p=0.05). Pre-culture, these SR CD4+CD25intCD45RO+ cells are unactivated (CD62Lhigh), 69.7% central memory (CCR7+,CD27+) and do not express IL-17 or IFNγ. However, following culture with PMA/ionomycin 76.7% of the generated IL-17+/ IFNγ - cells arise from the CD4+CD25intCD45RO+ predominantly CCR7+CD27+ subgroup.
Further to our previous data, we have further refined the phenotype of SR resistant cells to a CD4+CD25intCD45RO+ subset. Moreover, the propensity for these cells to express IL-17, suggests that they are a potential source of pathogenic SR Th17 cells in human autoimmune diseases such as non-infectious uveitis.
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