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A20 restrains thymic regulatory T cell development

(2017) JOURNAL OF IMMUNOLOGY. 199(7). p.2356-2365
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Abstract
Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T-reg) cells in the thymus. Activation of NF-kappa B transcription factors is critically required for T-reg cell development, partly via initiating Foxp3 expression. NF-kB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4(+) T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral T-reg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T-reg differentiation. A20-deficient thymic T-reg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-kappa B transcription factor Re1A was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic T-reg cells. Furthermore, we found that the increase in T-reg cells in T cell specific A20-deficient mice was already observed in CD4(+) single-positive CD25(+) GITR(+) Foxp3 thymic Treg cell progenitors. T-reg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T-reg cell development. A20-deficient T-reg cells efficiently suppressed effector T cell mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural T-reg cells in check, A20 thus integrates T-reg cell activity and increased effector T cell survival into an efficient CD4(+) T cell response.
Keywords
NF-KAPPA-B, SYSTEMIC-LUPUS-ERYTHEMATOSUS, DEUBIQUITINATING ENZYME CYLD, DIFFERENTIAL REQUIREMENT, TRANSCRIPTION FACTOR, FOXP3 EXPRESSION, KINASE, TAK1, TNFAIP3, ACTIVATION, SURVIVAL

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Chicago
Fischer, Julius Clemens, Vera Otten, Maike Kober, Christoph Drees, Marc Rosenbaum, Martina Schmickl, Simon Heidegger, et al. 2017. “A20 Restrains Thymic Regulatory T Cell Development.” Journal of Immunology 199 (7): 2356–2365.
APA
Fischer, J. C., Otten, V., Kober, M., Drees, C., Rosenbaum, M., Schmickl, M., Heidegger, S., et al. (2017). A20 restrains thymic regulatory T cell development. JOURNAL OF IMMUNOLOGY, 199(7), 2356–2365.
Vancouver
1.
Fischer JC, Otten V, Kober M, Drees C, Rosenbaum M, Schmickl M, et al. A20 restrains thymic regulatory T cell development. JOURNAL OF IMMUNOLOGY. 2017;199(7):2356–65.
MLA
Fischer, Julius Clemens et al. “A20 Restrains Thymic Regulatory T Cell Development.” JOURNAL OF IMMUNOLOGY 199.7 (2017): 2356–2365. Print.
@article{8533765,
  abstract     = {Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T-reg) cells in the thymus. Activation of NF-kappa B transcription factors is critically required for T-reg cell development, partly via initiating Foxp3 expression. NF-kB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4(+) T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral T-reg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T-reg differentiation. A20-deficient thymic T-reg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-kappa B transcription factor Re1A was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic T-reg cells. Furthermore, we found that the increase in T-reg cells in T cell specific A20-deficient mice was already observed in CD4(+) single-positive CD25(+) GITR(+) Foxp3 thymic Treg cell progenitors. T-reg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T-reg cell development. A20-deficient T-reg cells efficiently suppressed effector T cell mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural T-reg cells in check, A20 thus integrates T-reg cell activity and increased effector T cell survival into an efficient CD4(+) T cell response.},
  author       = {Fischer, Julius Clemens and Otten, Vera and Kober, Maike and Drees, Christoph and Rosenbaum, Marc and Schmickl, Martina and Heidegger, Simon and Beyaert, Rudi and van Loo, Geert and Li, Xian Chang and Peschel, Christian and Schmidt-Supprian, Marc and Haas, Tobias and Spoerl, Silvia and Poeck, Hendrik},
  issn         = {0022-1767},
  journal      = {JOURNAL OF IMMUNOLOGY},
  keywords     = {NF-KAPPA-B,SYSTEMIC-LUPUS-ERYTHEMATOSUS,DEUBIQUITINATING ENZYME CYLD,DIFFERENTIAL REQUIREMENT,TRANSCRIPTION FACTOR,FOXP3 EXPRESSION,KINASE,TAK1,TNFAIP3,ACTIVATION,SURVIVAL},
  language     = {eng},
  number       = {7},
  pages        = {2356--2365},
  title        = {A20 restrains thymic regulatory T cell development},
  url          = {http://dx.doi.org/10.4049/jimmunol.1602102},
  volume       = {199},
  year         = {2017},
}

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