Abstract
Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-κB transcription factors is critically required for Treg cell development, partly via initiating Foxp3 expression. NF-κB 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 Treg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic Treg differentiation. A20-deficient thymic Treg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-κB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic Treg cells. Furthermore, we found that the increase in Treg cells in T cell-specific A20-deficient mice was already observed in CD4+ single-positive CD25+ GITR+ Foxp3- thymic Treg cell progenitors. Treg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic Treg cell development. A20-deficient Treg 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 Treg cells in check, A20 thus integrates Treg cell activity and increased effector T cell survival into an efficient CD4+ T cell response.
Original language | English (US) |
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Pages (from-to) | 2356-2365 |
Number of pages | 10 |
Journal | Journal of Immunology |
Volume | 199 |
Issue number | 7 |
DOIs | |
State | Published - Oct 1 2017 |
Keywords
- Animals
- Apoptosis
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Flow Cytometry
- Forkhead Transcription Factors
- Gene Expression Regulation
- Glucocorticoid-Induced TNFR-Related Protein
- Graft vs Host Disease
- Interleukin-2
- Lymphocyte Activation
- Mice
- NF-kappa B
- Proto-Oncogene Proteins c-rel
- Signal Transduction
- Stem Cell Transplantation
- T-Lymphocytes, Regulatory
- Thymus Gland
- Transcription Factor RelA
- Tumor Necrosis Factor alpha-Induced Protein 3
- Journal Article
- Research Support, Non-U.S. Gov't