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Generation of Knock-out Primary and Expanded Human NK Cells Using Cas9 Ribonucleoproteins
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WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function.

Joshua T Piotrowski1, Timothy S Gomez, Renee A Schoon

  • 1Department of Immunology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Molecular and Cellular Biology
|January 1, 2013
PubMed
Summary

The Wiskott-Aldrich syndrome protein superfamily (WASH) is crucial for T cell proliferation and function. Its absence impairs recycling of key surface proteins, leading to reduced glucose uptake and metabolic output in T cells.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The Wiskott-Aldrich syndrome protein superfamily (WASH) is known to activate Arp2/3 and participate in endosomal trafficking.
  • Its specific in vivo function within T cells has remained largely unexamined.

Purpose of the Study:

  • To investigate the physiological role of WASH in T cell function using a conditional knockout mouse model.
  • To elucidate the impact of WASH deficiency on T cell activation, proliferation, and effector functions.

Main Methods:

  • Generation of a WASH conditional knockout (WASHout) mouse model utilizing CD4(Cre) deletion.
  • Analysis of thymocyte development, naive T cell activation, T cell receptor (TCR) signaling, and interleukin-2 production.
  • Assessment of T cell proliferative potential, experimental autoimmune encephalomyelitis induction, and surface protein levels (TCR, CD28, LFA-1, GLUT1).
  • Investigation of endosomal trafficking, glucose uptake, and metabolic output in WASHout T cells.

Main Results:

  • WASH deficiency did not affect thymocyte development or naive T cell activation, despite normal TCR signaling and IL-2 production.
  • WASHout T cells exhibited significantly reduced proliferative potential and impaired experimental autoimmune encephalomyelitis induction.
  • Activated WASHout T cells failed to maintain surface levels of TCR, CD28, LFA-1, and GLUT1 due to aberrant endosomal accumulation and lysosomal degradation.
  • Consequently, activated WASHout T cells showed reduced glucose uptake and metabolic output.

Conclusions:

  • WASH is a critical regulator of endosome-to-membrane recycling for key T cell proteins including TCR, CD28, LFA-1, and GLUT1.
  • Aberrant trafficking of these proteins in WASH-deficient T cells leads to attenuated proliferation and effector function.
  • WASH plays a newly recognized role in maintaining T cell metabolic fitness and functional capacity.