General autoimmunity

Poster

Regulation of B Lymphocyte Metabolism by the pi3k/akt Pathway

Thursday, June 15
5:45 PM - 7:00 PM

The phosphatidylinositol-3-kinase (PI3K) pathway has been shown to regulate cellular metabolism.  Disturbance of the PI3K pathway causes abnormal activation of immune cells that may result in autoimmunity or leukemia/lymphoma development.  Tandem pleckstrin homology (PH) domain proteins (TAPPs) bind to phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), a product of PI3K.  The serine/threonine kinase known as Akt is also recruited to PI(3,4)P2 where it becomes activated.  This results in the activation of signalling pathways that regulate many biological processes including cellular metabolism.  Here we investigate how the PI3K pathway and specifically how TAPP proteins control B lymphocyte activation. TAPP knock-in (KI) mice contain a knock-in mutation that results in TAPPs with a defective C-terminal PH domain, preventing its binding to PI(3,4)P2.  Using wild-type (Wt) and TAPP KI mice, we studied the effect of this mutation and how it impacted B cell metabolism. TAPP KI B cells exhibit increased proliferation, increased cell size and increased Akt phosphorylation upon activation in vitro.  These cells show elevated metabolic activity (measured by oxygen consumption rate and extracellular acidification rate), increased expression of glucose transporter Glut1 and increased glucose uptake.  Treatment of TAPP KI B cells with pharmaceutical inhibitors of PI3K decreased Glut1 expression and glucose uptake, and reduced proliferation.   TAPP KI mice develop B cell-mediated autoimmunity that could be partially reversed by treatment with the inhibitor of glycolysis 2-deoxyglucose.  Our data demonstrate that PI3K controls B cell metabolism, suggesting that targeting abnormal B cell metabolism may have therapeutic benefit.

Edgard Mejia

University of Manitoba/Dept. of Immunology

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    Nipun Jayachandran

    University of Manitoba/Dept. of Immunology

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      Kimia Sheikholeslami

      University of Manitoba/Dept. of Immunology

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        Sen Hou

        University of Manitoba/Dept. of Immunology

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          Grant Hatch

          University of Manitoba/Children's Hospital Research Institute of Manitoba

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            Aaron Marshall

            University of Manitoba/Dept. of Immunology

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