TCR triggering modulates the responsiveness and homeostatic proliferation of CD4+ thymic emigrants to IL-7 therapy

Blood. 2013 Jun 6;121(23):4684-93. doi: 10.1182/blood-2012-09-458174. Epub 2013 Apr 23.

Abstract

Interleukin-7 (IL-7) is currently used in clinical trials to augment T-cell counts. Paradoxically, elevated systemic IL-7 found in lymphopenic humans is typically insufficient for CD4(+) T-cell regeneration, and thymopoiesis becomes critical in this process. Here we show that the proliferative effect of IL-7 is more pronounced on CD4(+)CD8(-) thymocytes compared with peripheral CD4(+) T cells. These cells express miR181a at higher levels and respond to lower concentrations of IL-7. As single-positive CD4(+) thymocytes (CD4(+)(SPT)) exit the thymus, they rapidly diminish their proliferation to IL-7 therapy, and this is mediated, at least in part, by major histocompatibility complex class II distribution outside the thymus. Interestingly, increasing T-cell receptor (TCR) stimulation augments IL-7 responsiveness and proliferation of peripheral CD4(+) T cells, whereas failure to stimulate TCR abrogates proliferation induced by IL-7. Finally, we demonstrated that IL-7 enhances the proliferation of CD4(+) T cells that undergo "slow proliferation" in lymphopenic hosts. To date, our results indicate that TCR signaling is a major controlling factor for CD4 responsiveness and proliferation to IL-7 therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Flow Cytometry
  • Homeodomain Proteins / physiology
  • Homeostasis
  • Interleukin-7 / administration & dosage*
  • Interleukin-7 / pharmacology
  • Lymphocyte Activation
  • Lymphopenia / immunology*
  • Lymphopenia / metabolism
  • Lymphopenia / pathology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / drug effects
  • Thymus Gland / immunology*

Substances

  • Homeodomain Proteins
  • Interleukin-7
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • STAT5 Transcription Factor
  • mirn181 microRNA, mouse
  • RAG-1 protein