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Constitutively active STAT6 predisposes toward a lymphoproliferative disorder.

Mark H Kaplan1, Sarita Sehra, Hua-Chen Chang

  • 1Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. mkaplan2@iupui.edu

Blood
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Summary

Constitutively active Signal transducer and activator of transcription 6 (STAT6) in T cells predisposes mice to lymphoproliferative disorders, causing splenomegaly. This suggests STAT6 plays a role in T-cell malignancies.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Signal transducer and activator of transcription 6 (STAT6) is essential for T helper 2 (Th2) cell development and responses to interleukin-4 (IL-4) and IL-13.
  • Constitutively active STAT6 (STAT6VT) was expressed in T cells using the CD2 locus control region in genetically engineered mice.

Purpose of the Study:

  • To investigate the consequences of constitutive STAT6 activation in T cells.
  • To determine if STAT6 activation can induce lymphoproliferative disease (LPD).

Main Methods:

  • Generation of transgenic mice expressing constitutively active STAT6 (STAT6VT) under the CD2 locus control region.
  • Analysis of spleen size and cellular composition in STAT6VT mice.
  • Phenotypic characterization of spleen cell populations.

Main Results:

  • Approximately 5% of STAT6VT mice spontaneously developed lymphoproliferative disease (LPD) characterized by significant splenomegaly.
  • LPD spleen cell populations were either mixed lineage or predominantly T cells with phenotypes resembling autoimmune lymphoproliferative syndrome (ALPS).

Conclusions:

  • Constitutive STAT6 activation in T cells does not act as a transforming factor but predisposes to lymphoproliferative disorders.
  • STAT6 signaling plays a critical role in maintaining T-cell homeostasis and preventing aberrant proliferation.