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Induction of Alloantigen-specific Anergy in Human Peripheral Blood Mononuclear Cells by Alloantigen Stimulation with Co-stimulatory Signal Blockade
Published on: March 14, 2011
Targeting PKCθ in alloreactivity and graft-versus-host-disease: unanswered questions and therapeutic potential
Crystina C Bronk1, Xue-Zhong Yu, Amer A Beg
1Department of Immunology, Moffitt Cancer Center Tampa, FL, USA.
Abstract:
Protein kinase C isoform θ (PKCθ) is a key modulator of TCR signaling and mediates activation of NF-κB, NF-AT, and AP-1 transcription factors. Although in vitro studies of PKCθ(-/-) T cells have shown impaired activation responses, in vivo studies indicate that PKCθ requirement is not universal. While PKCθ is important in induction of experimentally induced autoimmune diseases in mice and generation of Th2 responses, it is not essential for induction of T cell proliferative and cytotoxic responses against influenza virus, LCMV, and vaccinia virus. The context-specific involvement of PKCθ in T cell responses suggests that inhibition of PKCθ may be beneficial in some but not all situations. In the bone marrow transplantation (BMT) setting, we have shown that graft-versus-host-disease (GVHD) cannot be induced in the absence of PKCθ. However, graft-versus-leukemia effects and T cell ability to clear virus infection remains intact. Therefore, PKCθ is a potential therapeutic target in BMT, inhibition of which may prevent GVHD while retaining anti-tumor and anti-infection responses.
Insights
Protein kinase C theta (PKCθ) plays a specific role in T cell responses. Inhibiting PKCθ may prevent graft-versus-host disease in bone marrow transplants while preserving anti-viral and anti-tumor immunity.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Protein kinase C theta (PKCθ) is a critical regulator of T cell receptor (TCR) signaling.
- PKCθ influences the activation of key transcription factors like NF-κB, NF-AT, and AP-1.
- While in vitro studies show impaired T cell responses in PKCθ-deficient cells, in vivo data reveal context-specific requirements for PKCθ.
Purpose of the Study:
- To investigate the role of PKCθ in T cell-mediated responses within the bone marrow transplantation (BMT) setting.
- To determine if PKCθ inhibition could selectively prevent graft-versus-host disease (GVHD) while maintaining graft-versus-leukemia (GVL) and anti-viral effects.
Main Methods:
- Utilized PKCθ knockout (PKCθ(-/-)) mouse models.
- Assessed T cell activation, proliferation, and cytotoxic responses in various experimental settings, including viral infections and BMT models.
- Evaluated the induction of GVHD and GVL effects in PKCθ(-/-) recipients and/or donors.
Main Results:
- PKCθ is essential for the induction of experimental autoimmune diseases and Th2 responses.
- T cell proliferative and cytotoxic responses against influenza virus, LCMV, and vaccinia virus are not dependent on PKCθ.
- Graft-versus-host-disease (GVHD) could not be induced in the absence of PKCθ.
- Graft-versus-leukemia (GVL) effects and the ability of T cells to clear viral infections remained intact in PKCθ-deficient settings.
Conclusions:
- PKCθ's involvement in T cell responses is context-dependent.
- PKCθ is a potential therapeutic target in BMT to prevent GVHD.
- Inhibition of PKCθ may offer a strategy to mitigate GVHD while preserving crucial anti-tumor and anti-infection immune functions.
