Are IL-10+ regulatory Th17 cells implicated in the sustained response to glucocorticoid treatment in patients with Giant Cell Arteritis? Comment on the paper of Espigol-Frigole et al.
We have read with interest the recently published paper of Espigol-Frigole et al. 1 in which the authors confirmed that IL-17 is highly expressed in giant cell arteritis (GCA) lesions.1-3 They also demonstrated for the first time that IL-17 expression in temporal artery biopsies (TAB) was correlated with a better outcome. Among other interesting results, the identification of Foxp3+IL-17+ T cells by confocal microscopy in TAB, made the authors to hypothesize that these cells could be induced-regulatory T cells (Treg) that may facilitate the remission of the disease under steroid therapy.
Evidence have been recently published regarding the plasticity of the different T helper subsets, such as Th1, Th17 and Treg cells that can differentiate into each other, depending on the cytokines produced in their microenvironment.4-6 Actually, Th17 cells with an anti-inflammatory phenotype have been described. This subset of Th17 cells express Foxp3 and produce IL-17, IL-10 but not IFN-gamma and exert regulatory functions.8,9 Their genesis is induced by the combination of IL-6 and TGF-beta.9 We have recently assessed TAB of GCA patients, showing also that Th17 cells highly infiltrated GCA lesions with only very few Treg.3 We have also confirmed that the percentage of circulating Th17 cells was increased in GCA.
In accordance with Espigol-Frigole, we hypothesized that a part of these Th17 cells could have been differentiated into regulatory cells secreting suppressive cytokines. Thus, we investigated the level of IL-10 in the serum of 19 patients affected by GCA and 28 healthy controls. IL-10 was measured by Luminex technology, as already described.3 Interestingly, the level of IL-10 was increased in the serum of patients affected by GCA, in comparison with healthy controls: mean +/- SEM was 2.6 +/- 0.74 vs. 0.91 +/- 0.33. Moreover, the level of IL-10, probably secreted by regulatory Th17 cells, was predictive of the outcome of the GCA patients. After a mean follow-up of 23.7 +/- 1.4 months, 4 patients experienced a relapse, 2 patients were corticosteroid dependent and the remission was sustained without relapse in 13 patients. Interestingly, IL-10 was significantly lower at the time of diagnosis in patients that experienced a relapse in comparison with patients without relapse (0.72 +/- 0.16 vs. 2.36 +/- 0.56 pg/mL; P = 0.0233).
Taken together, these results could explain the better outcome of patients expressing high levels of IL-17 in TAB. Espigol-Frigole et al have indeed demonstrated that Foxp3+ T cells contributed to the production of IL-17 in these patients. We hypothesize that these cells also produce IL-10 and match to a subset of anti-inflammatory Th17 cells characterized by an IL-10+Foxp3+IL-17+ phenotype. The better outcome of patients expressing high levels of IL-17 in GCA lesions could be linked to the amount of regulatory IL-10+Foxp3+IL-17+ T cells in GCA lesions rather than the level of conventional proinflammatory Th17 cells.
1. Espigol-Frigole G, Corbera-Bellalta M, Planas-Rigol E, et al. Increased IL-17A expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in patients with giant-cell arteritis. Ann Rheum Dis 2012.
2. Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010;121:906-15.
3. Samson M, Audia S, Fraszczak J, et al. Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis. Arthritis Rheum 2012;64:3788-98.
4. Annunziato F, Romagnani S. Heterogeneity of human effector CD4+ T cells. Arthritis Res Ther 2009;11:257.
5. Peck A, Mellins ED. Plasticity of T-cell phenotype and function: the T helper type 17 example. Immunology 2010;129:147-53.
6. Zhu J, Paul WE. Heterogeneity and plasticity of T helper cells. Cell Res 2010;20:4-12.
7. Bending D, De la Pena H, Veldhoen M, et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 2009;119:565-72.
8. Lochner M, Peduto L, Cherrier M, et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 2008;205:1381-93.
9. McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007;8:1390-7.
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