Coupled IL-2-dependent extracellular feedbacks govern two distinct consecutive phases of CD4 T cell activation

J Immunol. 2013 Dec 15;191(12):5822-30. doi: 10.4049/jimmunol.1301575. Epub 2013 Nov 15.

Abstract

T cells integrate cell-specific Ag receptor signaling with shared signals mediated by secreted cytokines, which often involve regulatory feedback loops. IL-2 signaling, for example, reduces the synthesis of IL-2 and increases the synthesis of IL-2Rα-chain, whereas both genes require TCR signaling for their activation. The ways by which T cells dynamically integrate these private and public signals during activation are not well understood. We combined robotics, multiparameter flow cytometry, and real-time quantitative PCR to analyze T cell activation at high temporal resolution over several days. Two distinct temporal phases of T cell activation were evident. First, Ag-dependent signals activated low IL-2Rα and high IL-2 production, independent of IL-2 signaling. Subsequently, secreted IL-2 acted as a shared resource driving high IL-2Rα expression, reduced IL-2 synthesis, and cell proliferation. This transition was independent of continued TCR signaling. Our data allowed the determination of the parameters of the IL-2-mediated extracellular positive and negative feedback circuits and demonstrated that the two loops are coupled and become activated at a similar level of IL-2 signaling. We propose that temporal separation of private and shared signals allows T cells to first integrate Ag-specific responses and subsequently share information leading to collective decision making.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Feedback, Physiological / physiology*
  • Flow Cytometry / methods
  • Gene Expression Regulation / immunology
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Interleukin-2 / physiology*
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Molecular Sequence Data
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell / immunology
  • Robotics
  • Time Factors

Substances

  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Antigen, T-Cell