Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: IL-21 activates mechanistic target of rapamycin (mTOR) complexes 1 and 2 which in turn block regulatory T (Treg)-cell differentiation and function in patients with SLE. While both IL-21 and IL-6 phosphorylate STAT3 in CD4+ T cells cultured under Treg-polarizing conditions, only IL-21 stimulates mTOR and abrogates Treg-cell differentiation in humans (Arthritis Rheumatol. 2018 Mar;70(3):427-438). This suggests that IL-21 blocks Treg-cell differentiation through an mTOR-dependent, but STAT3-independent mechanism. However, it remains unclear how IL-21-driven mTOR activation elicits Treg-cell depletion and dysfunction in SLE.
Methods: Naïve CD4+ T cells from 9 pairs of matched SLE and healthy control (HC) subjects were cultured for 24 hours in the presence of anti-CD3/CD28, TGF-β (5 ng/ml), and IL-2 (50 IU/ml) (hereafter designated Treg-polarizing conditions) with or without IL-21 (10 ng/ml). As a control, CD4+ T cells from 3 matched SLE and HC subjects were cultured for 72 hours in the presence of anti-CD3/CD28 and TGF-β (20 ng/ml) with or without IL-2 (100 IU/ml). Expression and phosphorylation of STAT5 at tyrosine 694 were detected by immunoblotting. The signal intensity of phospho-STAT5 was normalized to that of actin. Statistical significance was determined by a two-tailed t-test using GraphPad Prism version 5 software.
Results: IL-2 induced the phosphorylation of STAT5 in CD4+ T cells from patients with SLE (p< 0.005). Conversely, IL-21 suppressed STAT5 phosphorylation in naïve CD4+ T cells cultured under Treg-polarizing conditions both in HC and SLE subjects (p< 0.05). Following 24 hours of Treg polarization, CD4+ T cells from SLE patients exhibited diminished STAT5 phosphorylation as compared with those from HC subjects (p< 0.05).
Conclusion: In light of the essential roles for STAT5 in Treg-cell differentiation, our data suggests that IL-21-mediated suppression of STAT5 phosphorylation underlies the Treg-cell depletion and dysfunction in patients with SLE.
To cite this abstract in AMA style:Kato H, Perl A. IL-21-mediated Suppression of STAT5 Phosphorylation Underlies Treg Depletion and Dysfunction in SLE [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/il-21-mediated-suppression-of-stat5-phosphorylation-underlies-treg-depletion-and-dysfunction-in-sle/. Accessed January 27, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-21-mediated-suppression-of-stat5-phosphorylation-underlies-treg-depletion-and-dysfunction-in-sle/