Phosphatidylinositol 3-kinase improves the efficiency of positive selection

We have generated transgenic mice expressing the amino-terminal fragment of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110(ABD)) in thymocytes. Expression of P110(ABD) results in constitutive activation of PI3K and in significant increases in the numbers of mature, single-positive thymocytes. We previously reported that the increase in mature cells was in part due to a defect in thymic emigration. In this study we identify another component to this phenotype. Expression of p110(ABD) results in an enhancement of positive selection, without alterations in thymocyte lifespan or negative selection. Since PI3K can affect activation of Btk, which in turn potentiates calcium fluxes, during B cell development, our results suggest that PI3K could play a role in the regulation of Itk kinases in T cells, and that both cell types share a common signaling network to modulate calcium responses downstream of their antigen receptor

Gene transfer of RANTES elicits autoimmune renal injury in MRL-Faslpr mice

Infiltrating macrophages and T cells are instrumental in autoimmune kidney destruction of MRL-Faslpr mice. We report that the β-chemokine RANTES, a chemoattractant for macrophages and T cells, is up-regulated in the MRL-Faslpr kidney prior to injury, but not normal kidneys (MRL-++, C3H-++) and increases with progressive injury. Furthermore, we establish an association between RANTES expression in the kidney and renal damage using a gene transfer approach. Tubular epithelial cells genetically modified to secrete RANTES infused under the renal capsule incites interstitial nephritis in MRL-Faslpr, but not MRL-++ or C3H-++ mice. RANTES recruits predominantly macrophages (Mø) and CD4+ and CD8+ T cells. In contrast, gene transfer of CSF-1, another molecule up-regulated simultaneously with RANTES in MRL-Faslpr kidneys, promotes the influx of Mø, CD4+ T cells and the unique double-negative (DN) T cells (CD4-,CD8-), which are prominent in diseased MRL-Faslpr kidneys. Thus, RANTES and CSF-1 recruit distinct T cell populations into the MRL-Faslpr kidney. In addition, delivery of RANTES and CSF-1 into the kidney of MRL-Faslpr mice causes an additive increase in pathology. We suggest that the complementary recruitment of T cell populations by RANTES (CD4, CD8) and CSF-1 (CD4, DN) promotes autoimmune nephritis in MRL-Faslpr mice