NDLI: Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.

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Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Seddon, Benedict Tung, Sim Sinclair, Charles Marshall, Daniel
Description	Country affiliation: United kingdom Author Affiliation: Marshall D ( Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom.); Sinclair C ( Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom.); Tung S ( Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom.); Seddon B ( Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom benedict.seddon@ucl.ac.uk.)
Abstract	The developmental pathways of regulatory T cells (T(reg)) generation in the thymus are not fully understood. In this study, we reconstituted thymic development of Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection of T(reg) development. We find that T(reg) develop with distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models of CD25(+)Foxp3(+) T(reg) selection suggest development via CD25(+)Foxp3(-) CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25(-)Foxp3(+) cells that are highly efficient at maturing to CD25(+)Foxp3(+) cells in response to IL-2. CD25(-)Foxp3(+) cells more closely resembled mature T(reg) both with respect to kinetics of development and avidity for self-peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25(-)Foxp3(+) cells were IL-15 dependent, whereas generation of CD25(+)Foxp3(+) specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, whereas IL-2 was of exclusively from hemopoetic cells that depended on intact CD4 lineage development but not either Ag-experienced or NKT cells.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1402144
Journal	The Journal of Immunology
Issue Number	11
Volume Number	193
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Blood Cells Metabolism Interleukin-15 Interleukin-2 Stromal Cells T-lymphocytes, Regulatory Immunology Animals Antigens, Cd4 Cell Differentiation Cell Lineage Cells, Cultured Forkhead Transcription Factors Interleukin-2 Receptor Alpha Subunit Mice Mice, Inbred C57bl Mice, Knockout Transplantation Thymus Gland Transplantation Chimera Zap-70 Protein-tyrosine Kinase Genetics Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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IL-2R signaling is essential for functional maturation of regulatory T cells during thymic development.

IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development.

Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner.

Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells

B7-1 and B7-2 differentially control peripheral homeostasis of CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Intrathymic administration of hematopoietic progenitor cells enhances T cell reconstitution in ZAP-70 severe combined immunodeficiency.

Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages.

Molecular signature of recent thymic selection events on effector and regulatory CD4+ T lymphocytes.

Development of mouse CD4(+)CD25(+)Foxp3(+) regulatory T cells in xenogeneic pig thymic grafts.

Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.

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IL-2R signaling is essential for functional maturation of regulatory T cells during thymic development.

IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development.

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Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.