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Baoying Liu, Ashwin Dhanda, Zhiyu Li, Rafael Villasmil, Richard Lee, Robert Nussenblatt; Human monocyte subsets differentially drive T helper cell polarization: implications for the pathogenesis and treatment of autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2521.
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T helper 1 (Th1) and Th17 cells are thought to be the main pathogenic effectors in autoimmune uveitis. However, how human innate immunity interacts with adaptive immunity and whether this interaction contributes to uveitis pathogenesis are less well understood. Peripheral monocytes can be categorized into 3 groups: CD14dimCD16+; CD14highCD16-; and CD14highCD16+. We have previously reported that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype, and in this study we sought to investigate the effect this could have on T helper cell polarization.
Human peripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy donors using a Ficoll gradient centrifugation protocol. Untouched naïve and memory CD4+ T cells were isolated based on magnetic depletion protocols (Mitenyi Biotec). The subsets of monocyte described above were purified from the same donors by flow cytometry (BDFACSAria II) based on CD14 and CD16 staining. Each monocyte subset was then co-cultured in the presence of anti-CD3 with naïve or memory T cells for 5 days, after which T cell polarization was assessed by intracellular staining with anti-interferon γ (IFN γ, Th1) and anti-IL-17 (Th17). T cell activation was also monitored by CD25 surface staining.
CD14dimCD16+ monocytes were the only subset of monocytes to significantly increase CD25 expression on naïve CD4+ T cells. CD14dimCD16+ monocytes also polarized both naïve and memory CD4+ T cells in Th1 direction. The principal effect of CD14highCD16- monocytes was to polarize memory Th cells towards the Th17 phenotype.
In this study, which is the first to examine the effect of CD14dim cells on human CD4+ T cell polarization, we have demonstrated that human monocyte subsets differentially define both naïve and memory CD4+ T cell polarization. This highlights the critical role monocytes play in driving Th cell differentiation, and underlines their potential value, both for the stratification of disease, and as targets for immunomodulation in the treatment of human autoimmune uveitis.
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