Regulation of T cell alloimmunity by PI3K\u03b3 and PI3K\u03b4

Mayuko Uehara,David G Winkler,Stefan G Tullius,Martina M Mcgrath,Terry B Strom,Jamil Azzi,Abdallah Elkhal,Naima Banouni,Zhabiz Solhjou,Catherine Evans,Reza Abdi,Jonathan P Dinitto,Laurence A Turka,Sujit Routray,Shunsuke Ohori

doi:10.1038/s41467-017-00982-x

Abstract

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ−/− and PI3KδD910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ−/−, but not PI3ΚδD910A/D910A, recipients exhibit indefinite prolongation of heart allograft survival. PI3KδD910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.

Highlights

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation
To study the effect of PI3Kγ and PI3Kδ deletion on alloimmune responses in vivo, we injected 6 × 106 CD3+CD25− T cells isolated from splenocytes of PI3KδD910A/D910A, PI3Kγ−/−, or wild type (WT) naive mice, into RAG−/− recipients of BALB/c skin allograft at day 1 post-transplant (Fig. 1a)
There was a significant decrease in regulatory T cell (Treg) induction in mice receiving PI3KδD910A/D910A compared to WT CD3+CD25− T cells (27.60% ± 4.07% vs. 39.35% ± 5.05%, respectively, p = 0.05, t-test, n = 3/group) (Fig. 1d)

Summary

Introduction

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation. The γ and δ catalytic forms of PI3K are preferentially enriched in leukocytes and, through their capacity to regulate the function of immune cells[5, 7,8,9,10], represent a promising drug target for the treatment of inflammatory diseases. We show for the first time the role of PI3Kγ and PI3Kδ pathways in determining the fate of alloimmune responses

Methods

Results

Conclusion