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

J Immunol. 2014 Dec 1;193(11):5525-33. doi: 10.4049/jimmunol.1402144. Epub 2014 Oct 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Cells / metabolism*
  • CD4 Antigens / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • Forkhead Transcription Factors
  • Interleukin-15 / metabolism*
  • Interleukin-2 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Stromal Cells / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation
  • Thymus Gland / immunology
  • Transplantation Chimera
  • ZAP-70 Protein-Tyrosine Kinase / genetics

Substances

  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-15
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse