Juliet L. Emery

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Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production

PLoS ONE (2016)

Ariana Barberá Betancourt Juliet L. Emery Asha Recino F. Susan Wong Anne Cooke

Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.

Adoptive Cell Transfer

Phosphoinositide 3-kinase

10.1371/journal.pone.0146516

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Citations (5)

The PI3K Isoforms p110α and p110δ Are Essential for Pre–B Cell Receptor Signaling and B Cell Development

Science Signaling (2010)

Faruk Ramadani Daniel J. Bolland Fabien Garçon Juliet L. Emery Bart Vanhaesebroeck

Different isoforms of phosphatidylinositol 3-kinase have distinct roles in B cell receptor signaling.

P110α

Cell Signaling

10.1126/scisignal.2001104

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Citations (191)

CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer

Blood (2007)

Fabien Garçon Daniel T. Patton Juliet L. Emery Emilio Hirsch Robert Rottapel

Immunological synapse

10.1182/blood-2007-08-108050

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Citations (137)

Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells

Blood (2005)

Antonio Bilancio Klaus Okkenhaug Montserrat Camps Juliet L. Emery Thomas Rückle

10.1182/blood-2005-07-3041

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Citations (215)

Proliferative signals mediated by CD28 superagonists require the exchange factor Vav1 but not phosphoinositide 3‐kinase in primary peripheral T cells

European Journal of Immunology (2008)

Tea Gogishvili Fernando Elı́as Juliet L. Emery Kirsty McPherson Klaus Okkenhaug

Abstract Almost all responses of naive T cells require co‐stimulation, i.e. engagement of the clonotypic TCR with relevant antigen/MHC and the co‐stimulatory molecule CD28. How CD28 contributes to T‐cell proliferation remains poorly understood, with widely conflicting reports existing which may reflect different methods of co‐ligating receptors. Some CD28 mAb, however, can stimulate T‐cell proliferation without the need for TCR co‐ligation, and thus provide unique tools to dissect proliferative signals mediated through CD28 alone. Using primary peripheral T cells from CD28‐transgenic mice, we show that both the YMNM and Lck‐binding motifs, but not the Itk‐binding motif, in CD28 are required for proliferation. Given that the YMNM motif recruits both phosphoinositide 3‐kinase (PI3K) and the exchange factor Vav1, we investigated the role of these two molecules in CD28‐mediated proliferation. In p110δ D910A/D910A transgenic T cells, which are defective in PI3K activation following CD28 ligation, proliferation was comparable to that in wild‐type cells. By contrast, T‐cell proliferation was abolished in Vav1 −/− cells. Although we did not address the role of Grb2 in CD28 signalling, these results indicate that CD28 can mediate Lck‐ and Vav1‐dependent proliferative signals independently of PI3K.

Phosphoinositide 3-kinase

10.1002/eji.200838223

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Citations (14)