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WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function
Journal article   Open access   Peer reviewed

WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function

Joshua T Piotrowski, Timothy S Gomez, Renee A Schoon, Ashutosh K Mangalam and Daniel D Billadeau
Molecular and cellular biology, Vol.33(5), pp.958-973
03/2013
DOI: 10.1128/MCB.01288-12
PMCID: PMC3623087
PMID: 23275443
url
https://europepmc.org/articles/pmc3623087View
Published (Version of record) Open Access

Abstract

WASH is an Arp2/3 activator of the Wiskott-Aldrich syndrome protein superfamily that functions during endosomal trafficking processes in collaboration with the retromer and sorting nexins, but its in vivo function has not been examined. To elucidate the physiological role of WASH in T cells, we generated a WASH conditional knockout (WASHout) mouse model. Using CD4(Cre) deletion, we found that thymocyte development and naive T cell activation are unaltered in the absence of WASH. Surprisingly, despite normal T cell receptor (TCR) signaling and interleukin-2 production, WASHout T cells demonstrate significantly reduced proliferative potential and fail to effectively induce experimental autoimmune encephalomyelitis. Interestingly, after activation, WASHout T cells fail to maintain surface levels of TCR, CD28, and LFA-1. Moreover, the levels of the glucose transporter, GLUT1, are also reduced compared to wild-type T cells. We further demonstrate that the loss of surface expression of these receptors in WASHout cells results from aberrant accumulation within the collapsed endosomal compartment, ultimately leading to degradation within the lysosome. Subsequently, activated WASHout T cells experience reduced glucose uptake and metabolic output. Thus, we found that WASH is a newly recognized regulator of TCR, CD28, LFA-1, and GLUT1 endosome-to-membrane recycling. Aberrant trafficking of these key T cell proteins may potentially lead to attenuated proliferation and effector function.
 Wiskott-Aldrich Syndrome Protein - genetics Cell Proliferation Glucose Transporter Type 1 - immunology Encephalomyelitis, Autoimmune, Experimental - immunology Glucose Transporter Type 1 - metabolism Lymphocyte Function-Associated Antigen-1 - metabolism CD28 Antigens - metabolism Lymphocyte Function-Associated Antigen-1 - immunology Interleukin-2 - immunology T-Lymphocytes - metabolism Gene Deletion Receptors, Antigen, T-Cell - immunology Encephalomyelitis, Autoimmune, Experimental - genetics Microfilament Proteins - genetics Vesicular Transport Proteins - immunology CD4 Antigens - genetics CD4 Antigens - immunology Receptors, Antigen, T-Cell - metabolism Lymphocyte Activation Vesicular Transport Proteins - genetics Cells, Cultured CD28 Antigens - immunology Mice, Knockout Protein Transport Animals T-Lymphocytes - cytology Wiskott-Aldrich Syndrome Protein - immunology Microfilament Proteins - immunology Glycolysis T-Lymphocytes - immunology Mice

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