Session Time: 8:30am-9:45am
Presentation Time: 8:30am-8:45am
Location: Terrace Ballroom 1, 2, 3
Targeting survival pathways that differentially suppress effector T cells (Teff) while sparing regulatory T cells (Tregs) is key in devising novel tolerogenic protocols in transplantation. We previously showed that PI3K pathway, a major survival pathway, is highly activated in Teff compared to Tregs which suggested a differential role of PI3K in their survival. Here we studied the role of its leukocyte-restricted γ and δ subunits in Teff and Tregs homeostasis in alloimmunity. Generated Foxp3-GFP PI3Kγ and PI3Kδ Knockout mice (C57BL/6 background) were used in heart transplant models and GVHD models. Multiple experiments were done using FACS sorting, Flow and phosphoflow, ELISpot, Luminex and Western Blot assays. While PI3Kγ-/- and PI3Kδ-/- recipients of BALB/c hearts exhibited significant heart survival prolongation compared to WT (MST 14, 14 and 7 respectively, n=6/group, p<0.05), the administration of low dose CTLA4Ig (250¯o;g on day 2) induced indefinite allograft survival of the PI3Kγ-/- recipients compared to WT (MST >100 and 30 respectively, n=6/group, p<0.05) with a marked increase in Tregs and a reduced % of CD4+ and CD8+ Teff along with significant suppression of Th1/Th17 cytokines in the spleen and draining lymphondes (DLN). Surprisingly, the absence of PI3Kδ abrogated the effect of CTLA4Ig treatment with a marked decrease in Tregs with significant increase in CD4+ and CD8+ Teff in the spleen and DLN of the PI3Kδ-/- recipients along with significant upergulation of Th1/Th17 cytokines. Interestingly, Thymus of PI3Kδ-/- showed more than 3 fold increase in Tregs compared to PI3Kγ-/- and WT. Adoptive transfer of FoxP3-GFP-PI3Kδ-/- and FoxP3-GFP-PI3Kγ-/- Tregs into a GVHD model showed that PI3Kδ-/- Tregs went more into apoptosis compared to PI3Kγ-/- and WT Tregs. Furthermore, PI3Kδ-/- Tregs had lower MFI of FoxP3 compared to PI3Kγ-/- and WT Tregs. PI3Kγ-/- expressed higher level of CTLA4, PD1 TIM3 compared to PI3Kδ-/- and WT Tregs. Those markers correlate with better suppressive function. Moreover, PI3Kγ-/- but not PI3Kδ-/- exhibited significant induction of Tregs in vitro through activation of the CREB pathway as shown by western blot. Inhibition of CREB prevented Treg induction under PI3Kγ inhibition. Our data shows a differential role of PI3Kγ and PI3Kδ in Tregs homeostasis and function with significant application in future of PI3K based therapies in solid organ transplantation.
To cite this abstract in AMA style:Azzi J, Uehara M, Solhjou Z, Lukyanchykov P, Radwan A, Riella L, Abdi R. Differential Role of PI3K Subunits Gamma and Delta in Regulatory T Cells Homeostasis in Allotransplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/differential-role-of-pi3k-subunits-gamma-and-delta-in-regulatory-t-cells-homeostasis-in-allotransplantation/. Accessed December 4, 2020.
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