| First Author | Fischer JC | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 7 | Pages | 2356-2365 |
| PubMed ID | 28842469 | Mgi Jnum | J:251495 |
| Mgi Id | MGI:6103073 | Doi | 10.4049/jimmunol.1602102 |
| Citation | Fischer JC, et al. (2017) A20 Restrains Thymic Regulatory T Cell Development. J Immunol 199(7):2356-2365 |
| abstractText | Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-kappaB transcription factors is critically required for Treg cell development, partly via initiating Foxp3 expression. NF-kappaB 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-kappaB 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. |
