CD161 expression characterizes a sub-population of human regulatory T cells that produces IL-17 in a STAT3 dependent manner

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are “plastic”, and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. “IL-17 potential” is restricted to population III (CD4(+)CD25(hi)CD127(lo)CD45RA(−)) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary

The PI3-kinase/Akt signalling pathway influences integrin adhesion in lymphocytes

Aims: Death Receptor 3 (DR3), the closest tumour necrosis factor receptor superfamily relative to TNFR1, is essential for the accumulation and function of effector T cells in multiple autoimmune and inflammatory disease models, and the development of bone erosions late in animal models of inflammatory arthritis. Here, we investigated the role of DR3 in cartilage destruction during early stages of disease. Methods: DR3-deficient (DR3 KO ) and DR3WT littermates were induced for antigen-induced arthritis (AIA) using methylated BSA. Joints were sectioned and analysed for cartilage destruction using histo- and immunohistochemistry at early (3 days) and late (21 days) timepoints after intra-joint mBSA challenge. MMP-9 ELISAs were performed for in vitro culture experiments. Results: Resistance to cartilage destruction in DR3 KO mice was observed even at early timepoints (17.3% versus 1.9%, DR3WT versus DR3 KO , respectively; P = 0.03), prior to the main accumulation of effector T cells and macrophages into the joint. DR3 KO joints exhibited reduced levels of Ly6G + neutrophils (5.3% versus 1.3%, DR3WT versus DR3 KO , respectively; P = 0.001) and the cartilage-destroying enzyme, matrix metalloproteinase 9 (5.0% versus 2.5%, DR3WT versus DR3 KO , respectively; P = 0.04). In vitro experiments with human cells showed that TL1A, DR3’s only confirmed ligand, did not trigger MMP-9 release, but neutrophils produced >350 times more MMP-9 on a per cell basis than macrophages or fibroblasts (253 500 versus 690 versus 80 pg/h/ 10 6 cells; neutrophils versus macrophages versus RA synovial fibroblasts, respectively). Conclusions: DR3 controls early innate immune-driven development of cartilage destruction in inflammatory arthritis by regulating MMP-9 production and neutrophil accumulation

Representação: palavras, instituições e idéias Representation: words, institutions and ideas

Em argumento reconstrutivo, baseado em abordagem própria à filosofia da linguagem, a autora lança mão das transformações seculares nos usos da fala, nas cristalizações ideológicas no plano da filosofia política e nas práticas históricas de representação política para mostrar a emergência das feições distintivas da representação moderna.<br>In a reconstructive analysis, based upon the philosophy of language, the author handles the secular transformations in speech, ideological crystallizations within the tradition of political philosophy and the historical practices of political representation in order to show the coming up of the distinctive features of modern representation