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Chengrong Yu, Hyun-Mee Oh, Nady Golestaneh, Ahjoku Amadi-Obi, Yun Sang Lee, Essonu Amarachi, Rashid Mahdi, Charles Egwuagu; Th17 Cells Constitutive Produce Low Levels Of Il-2 That Induces Homeostatic Expansion Of Th17 And Confers Protection From Activation Induced Cell Death (aicd). Invest. Ophthalmol. Vis. Sci. 2011;52(14):2916.
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IL-2 plays a pivotal in the proliferation or survival of Th1, Th2 and Treg subsets and the expansion of human Th17 cells. It is therefore puzzling that IL-2 inhibits differentiation and expansion of mouse Th17 cells. A recent study showing that differentiating Th17 constitutively express IL-2 (Th17-DP) at early stage of their development but lose their capacity to produce IL-2 in matured Th17 cells further confounds the function of IL-2 in Th17 cells. Here, we sought to better understand the exact role of IL-2 in mouse Th17 cells.
Human CD4+ T cells are stimulated with anti-CD3/CD28 Abs in the presence or absence with IL-2, -6, and -23, anti-IL-2 Ab or Daclizumab. ELISA or intracellular cytokine staining are for cytokine detection. Lymph node, blood, or retinal cells are isolated from day-14, -18, -21, and -28 after AEU induction for Th17-DP detection and their RNA is isolated for RT-PCR. Naïve CD4+ T cells are polarized in Th1 and Th17 conditions in presence or absence of IL-2, IL-23, or anti-IL-2 neutralizing Ab. CFSE labeling and Annexin-V staining are for cell proliferation and apoptosis detection.
Human memory Th17 cells constitutively express IL-2. Blocking IL-2 signaling with anti-IL-2 neutralizing Ab or Daclizumab substantially inhibited their expansion. Increase in Th17-DP cells in lymph node, blood and retina correlated with development of experimental autoimmune uveitis (EAU) and constitutive expression of very low levels of IL-2 by Th17-DP allowed them to avoid AICD, persist in the retina and contribute to chronic inflammation in the retina.
The constitutive expression of low levels of IL-2 by Th17-DP has dual roles in Th17 cells. The low IL-2 levels allow Th17 cells to escape AICD while promoting their homeostatic expansion and these features of Th17 cells confers survival advantages to Th17 cells and may contribute to their frequent involvement in chronic inflammatory diseases.
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