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Haploinsufficiency of PTEN augments the chemotactic response of lymphocytes, alters gene expression, and results in autoimmunity

University of British Columbia

The ability of the cell to respond to physiological cues and integrate signals from outside sources is important for normal cellular function. The generation of second messengers is a central mechanism by which the cell activates signal transduction cascades that mediate cellular responses. Phosphatidylinositol lipid species (PIP) act as important second messengers in the membrane. Phosphatidylinositol-3-kinase (PI3K) and PTEN are responsible for regulating levels of PIP species and thus, are implicated in the control of many important cellular processes. Regulation of cellular activation is particularly important in the immune system where abnormal activation of lymphocytes can lead to developmental defects, impaired ability to defend against infection, and disease. In support of this, we and others have demonstrated that mice lacking a single allele of Pten develop an autoimmune disease that worsens with age. We observed increased lymph node size, splenomegaly, and elevated levels of serum immunoglobulins in Pten +/- mice. No evidence of major developmental defects were found in Pten +/- lymphocytes, however increased responsiveness of both B and T cells was detected. In the immune system, migration to specialized microenvironments ensures the proper development, differentiation, survival, elimination and activation of lymphocytes. The complex network of celhcell interactions that occurs during an immune response is also controlled by migratory events. Thus, we examined the role of Pten in the control of lymphocyte migration. We found that Pten +/- lymphocytes had an augmented chemotactic response to stromal cell derived factor-1 (SDF-1). We also demonstrated increased phosphorylation of protein kinase B (PKB) in response to SDF-1. Stimulation of lymphocytes with SDF-1 led to changes in gene expression. The expression of a subset of genes was altered in Pten +/- T cells. These observations provide evidence of a regulatory role for PTEN in lymphocytes and implicate PTEN in the dysregulation of the immune system that occurs during autoimmunity.

Thesis/Dissertation

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2009-11-13

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http://hdl.handle.net/2429/14910

Genetics

University of British Columbia

UBCV

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