Thymocyte apoptosis drives the intrathymic generation of regulatory T cells
Maintenance of immune tolerance critically depends upon regulatory T cells that express the transcription factor forkhead box P3 (Foxp3). These CD4 ⁺ T cells can be generated in the thymus, termed thymus-derived regulatory T cells (tTregs), but their developmental pathway remains incompletely unders...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 4; pp. E465 - E473 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
28.01.2014
National Acad Sciences |
Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Summary: | Maintenance of immune tolerance critically depends upon regulatory T cells that express the transcription factor forkhead box P3 (Foxp3). These CD4 ⁺ T cells can be generated in the thymus, termed thymus-derived regulatory T cells (tTregs), but their developmental pathway remains incompletely understood. tTreg development has been shown to be delayed compared with that of CD4 ⁺ single positive (SP) thymocytes, with tTregs being detected only in neonatal thymi by day 3 after birth. Here, we outline the reasons for this delayed emergence of Foxp3 ⁺ tTregs and demonstrate that thymocyte apoptosis is intrinsically tied to tTreg development. We show that thymic apoptosis leads to the production of TGFβ intrathymically from thymic macrophages, dendritic cells, and epithelial cells. This TGFβ then induces foxp3 expression and drives tTreg generation. Thymocyte apoptosis has previously been shown to accelerate after birth, which drives increases in TGFβ in the neonatal thymus. We highlight a paucity of TGFβ in the neonatal thymus, accounting for the delayed development of tTregs compared with CD4 ⁺ SP thymocytes. Importantly, we show that enhanced levels of apoptosis in the thymus result in an augmented tTreg population and, moreover, that decreasing thymic apoptosis results in reduced tTregs. In addition to this, we also show that T-cell receptor (TCR) signals of different affinity were all capable of driving tTreg development; however, to achieve this TGFβ signals must also be received concomitant with the TCR signal. Collectively, our results indicate that thymic apoptosis is a key event in tTreg generation and reveal a previously unrecognized apoptosis–TGFβ–Foxp3 axis that mediates the development of tTregs. |
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Bibliography: | http://dx.doi.org/10.1073/pnas.1320319111 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Edited by Philippa Marrack, Howard Hughes Medical Institute, National Jewish Health, Denver, CO, and approved December 18, 2013 (received for review October 28, 2013) Author contributions: J.E.K. and W.C. designed research; J.E.K., W.J., B.A., and J.R.G. performed research; J.E.K. and W.C. analyzed data; and J.E.K. and W.C. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1320319111 |