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Updated: Jul 19, 2026

Development of Stem Cell-derived Antigen-specific Regulatory T Cells Against Autoimmunity
Published on: November 8, 2016
Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ.
Mayuko Uehara1, Martina M McGrath1, Shunsuke Ohori1
1Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.
Targeting Phosphatidylinositol-3-kinases (PI3K) γ and δ in T cells impacts heart transplant rejection. PI3Kγ inhibition may enhance long-term allograft survival, offering potential for new transplantation therapies.
Area of Science:
- Immunology
- Transplantation Biology
- Molecular Signaling
Background:
- Phosphatidylinositol-3-kinases (PI3K) γ and δ are crucial for leukocyte signaling and T cell activation.
- The specific roles of PI3Kγ and PI3Kδ in alloimmunity and transplantation are not fully understood.
Purpose of the Study:
- To investigate the impact of PI3Kγ and PI3Kδ on T cell responses in heart allograft recipients.
- To explore the potential of PI3K inhibition as a therapeutic strategy for improving transplant outcomes.
Main Methods:
- Utilized PI3Kγ knockout (PI3Kγ-/-) and PI3Kδ mutant (PI3KδD910A/D910A) mouse models for heart transplantation.
- Administered low-dose CTLA4-Ig treatment to assess long-term allograft survival.
- Employed selective PI3Kγ, PI3Kδ, and dual PI3Kγδ chemical inhibitors.
Main Results:
- Both PI3Kγ-/- and PI3KδD910A/D910A mice showed suppressed alloreactive T effector cells and delayed acute rejection.
- PI3Kδ deficiency impaired regulatory T cell (Treg) survival and function.
- PI3Kγ-/- recipients, but not PI3KδD910A/D910A recipients, achieved indefinite heart allograft survival after CTLA4-Ig treatment.
- Selective PI3Kγ inhibition compensated for the negative effects of PI3Kδ inhibition on long-term allograft survival.
Conclusions:
- PI3Kγ and PI3Kδ play distinct roles in T cell-mediated alloimmunity and heart allograft rejection.
- Targeting PI3Kγ may offer a promising approach to enhance long-term allograft survival, particularly in combination with therapies like CTLA4-Ig.
- These findings provide a rationale for developing PI3K-based immunotherapies for transplantation.
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