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Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells
Open accessAbstract
Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of Treg cells. Conversely, TNFRSF agonists enhanced the differentiation of Treg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the Treg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of Treg cells. Thus, expression of members of the TNFRSF on Treg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of Treg cells and shaped the Treg cell repertoire.
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Citations
Cited by
T cell receptor signalling in the control of regulatory T cell differentiation and function
Li, M. O., & Rudensky, A. Y. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2016.26 · Cited by 493
The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond
Dostert, C., Grusdat, M., Letellier, E., & Brenner, D. (2019) · Physiological Reviews · doi:10.1152/physrev.00045.2017 · Cited by 498
The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses
Ward-Kavanagh, L. K., Lin, W. W., Šedý, J. R., & Ware, C. F. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.019 · Cited by 463
Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR
Zemmour, D., Zilionis, R., Kiner, E., Klein, A. M., Mathis, D., & Benoist, C. (2018) · Nature Immunology · doi:10.1038/s41590-018-0051-0 · Cited by 384
Savage, P. A., Klawon, D. E. J., & Miller, C. H. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-100219-020937 · Cited by 321
Metadata
- Authors
- Mahmud, S. A., Manlove, L. S., Schmitz, H. M., Xing, Y., Wang, Y., Owen, D. L., Schenkel, J. M., Boomer, J. S., Green, J. M., Yagita, H., Chi, H., Hogquist, K. A., & Farrar, M. A.
- Venue
- Nature Immunology
- Published
- 2014-03-16
- Volume
- 15
- Issue
- 5
- Pages
- 473-481
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2021249461
- Cited by
- 281
- References
- 0
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- green
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- Mahmud, S. A., Manlove, L. S., Schmitz, H. M., Xing, Y., Wang, Y., Owen, D. L., Schenkel, J. M., Boomer, J. S., Green, J. M., Yagita, H., Chi, H., Hogquist, K. A., & Farrar, M. A. (2014). Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nature Immunology. https://doi.org/10.1038/ni.2849
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