Increased phosphoinositide 3‐kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo

Abstract

Alterations in the cell division:cell death ratio induce multiple autoimmune and transformation processes. Phosphoinositide 3-kinase (PI3K) controls cell division and cell death in vitro, but its effect on the function of the cellular immune system and on tumor formation in mammals is poorly characterized. Here we show that transgenic mice expressing in T lymphocytes an active form of PI3K derived from a thymic lymphoma, p65(PI3K), developed an infiltrating lymphoproliferative disorder and autoimmune renal disease with an increased number of T lymphocytes exhibiting a memory phenotype and reduced apoptosis. This pathology was strikingly similar to that described in mice exhibiting heterozygous loss of the tumor suppressor PTEN, a lipid and protein phosphatase. We show that overexpression of PTEN selectively blocks p65(PI3K)-induced 3T3 fibroblast transformation. Moreover, the early development of T cell lymphomas in p65(PI3K) Tg p53(-/-) mice indicated that PI3K contributes to tumor development. These observations demonstrate that constitutive activation of PI3K extends T cell survival in vivo, affects T cell homeostasis, and contributes to tumor generation, supporting a model in which selective increases in one type of PTEN substrate, the PI3K-derived lipid products, induce tumorigenesis. PI3K thus emerges as a potential target in autoimmune disease and cancer therapy.

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

“…Immunopathology of Pten +/À mice was worsened when both alleles of Pten were deleted in the T-cell compartment. 20 Additionally, mice expressing a constitutively active form of PI3K specifically in T cells developed a phenotype similar to that of Pten +/À mice, 21 providing further evidence that the deregulation of phosphatidylinositol levels in this cell type can promote the development of autoimmunity.…”

Phosphatidylinositol 3-Kinase Regulates the CD4/CD8 T Cell Differentiation Ratio

“…Mice p65 PI3K transgenic (Tg) mice were generated as described (24). The Tg colony was maintained by crosses with C57BL/6 females, and offspring were analyzed by PCR 30 days after birth.…”

“…F5 TCR Tg mice were also crossed with p110␥ null mice. Offspring were analyzed by PCR as described (24) and by flow cytometry to verify the appropriate TCR and MHC. All mice were bred and maintained under specific pathogen-free conditions at the National Center for Biotechnology animal facility.…”

“…Mice remain healthy for 1 year; however, at ϳ12-15 mo of age, p65 PI3K induces development of a lymphoproliferative disease caused by the enhanced memory cell survival (24). This enhanced memory cell survival in adult mice does not explain the 30% increase in CD4 ϩ T cells in young mice.…”

A 50‐Year‐Old Woman With Cowden Syndrome and Joint Pains

“…CD4, CD8, and B cells from these mice show an activated phenotype and exhibit defective Fas-mediated apoptosis that is restored by wortmannin treatment (PI3K inhibitor) (8)(9)(10). Similarly, mice expressing an activated form of PI3K in T lymphocytes develop anti-dsDNA and immune complex glomerulonephritis-like SLE (11). PTEN plays an important role in regulatory T cells (T reg ) activity, function, and homeostasis.…”