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mTORC2 deficiency in cutaneous dendritic cells potentiates CD8+ effector T cell responses and accelerates skin graft

Alicia R Watson1,2, Helong Dai1,3, Julio A Diaz-Perez4

  • 1Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
|August 22, 2018
PubMed

Insights

Mechanistic target of rapamycin complex 2 (mTORC2) in dendritic cells restrains CD8+ T cell responses. Deleting mTORC2 in dendritic cells accelerates skin graft rejection by enhancing T cell immunity.

Area of Science:

  • Immunology
  • Cell Biology
  • Transplantation Science

Background:

  • Mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are critical regulators of immune cell differentiation and function.
  • While mTORC1 inhibition impacts dendritic cell (DC) differentiation and graft rejection, mTORC2's role in DCs regarding transplanted tissue responses is unclear.

Purpose of the Study:

  • To investigate the role of mTORC2 specifically in CD11c+ dendritic cells (DCs) in the context of immune responses to transplanted tissues.
  • To determine how the absence of mTORC2 in DCs influences T cell responses and graft rejection.

Main Methods:

  • Utilized a mouse model with mTORC2 specifically deleted in CD11c+ DCs (TORC2DC-/-).
  • Assessed the rejection of minor histocompatibility antigen (HY)-mismatched and MHC-mismatched skin grafts from TORC2DC-/- donors into wild-type recipients.
  • Evaluated CD8+ T cell responses in grafts and lymphoid tissues.
  • Examined a delayed-type hypersensitivity model with mTORC2-deficient cutaneous DCs.
  • Compared responses using ovalbumin transgenic skin grafts in TORC2DC-/- recipients.

Main Results:

  • Transplantation of skin grafts from TORC2DC-/- donors into wild-type recipients led to accelerated rejection.
  • This accelerated rejection was associated with enhanced CD8+ T cell responses in the graft and regional lymphoid tissue.
  • Similar augmentation of CD8+ effector T cell responses was observed in MHC-mismatched recipients.
  • Increased T cell stimulatory capacity of TORC2DC-/- DCs, not enhanced lymph node homing, accounted for the elevated responses.
  • Rejection of ovalbumin transgenic skin grafts in TORC2DC-/- recipients was not affected.

Conclusions:

  • mTORC2 signaling within skin dendritic cells acts as a brake on effector CD8+ T cell responses.
  • These findings have significant implications for understanding the impact of mTOR inhibitors targeting mTORC2 in transplantation settings.
Keywords:
antigen presentation/recognitionbasic (laboratory) research/sciencecellular biologydendritic celldermatologyimmunobiologyimmunosuppressant - mechanistic target of rapamycin (mTOR)

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