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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer*
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Animals
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Gene Expression Regulation
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Immunization
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Immunophenotyping
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Interleukin-2 / genetics*
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Interleukin-2 / immunology
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Interleukin-2 Receptor alpha Subunit / genetics*
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Interleukin-2 Receptor alpha Subunit / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Immunological
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Ovalbumin / administration & dosage
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / immunology
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Signal Transduction
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Single-Cell Analysis
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / transplantation
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / transplantation
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
Substances
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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STAT5 Transcription Factor
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Ovalbumin
Grants and funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.