Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

Elife. 2016 Dec 30;5:e20616. doi: 10.7554/eLife.20616.

Abstract

The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digital) and CD25 is graded expressed whereas at population level both parameters show graded expression correlating with the antigen amount. Combining in vivo data with a mathematical model we demonstrate that only this binary IL-2 expression ensures a wide linear antigen response range for Teff and Treg cells under real spatiotemporal conditions. Furthermore, at low antigen concentrations binary IL-2 expression safeguards by its spatial distribution selective STAT5 activation only of closely adjacent Treg cells regardless of their antigen specificity. These data show that the mode of IL-2 secretion is critical to tailor the adaptive immune response to the antigen amount.

Keywords: TCR signaling; Th cell activation; adaptive immune response; computational biology; cytokine expression; immunology; mouse; reaction-diffusion model; systems biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer*
  • Animals
  • Gene Expression Regulation
  • Immunization
  • Immunophenotyping
  • Interleukin-2 / genetics*
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor alpha Subunit / genetics*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Immunological
  • Ovalbumin / administration & dosage
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology
  • Signal Transduction
  • Single-Cell Analysis
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / transplantation
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / transplantation
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • STAT5 Transcription Factor
  • Ovalbumin

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.