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PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice
Javier O. Valenzuela, … , Xue-Zhong Yu, Amer A. Beg
Javier O. Valenzuela, … , Xue-Zhong Yu, Amer A. Beg
Published November 9, 2009
Citation Information: J Clin Invest. 2009;119(12):3774-3786. https://doi.org/10.1172/JCI39692.
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Research Article Immunology Article has an altmetric score of 7

PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

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Abstract

When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform θ (PKCθ), a key regulator of TCR signaling. In contrast, PKCθ was required for alloreactivity and GVHD induction. Furthermore, absence of PKCθ raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCθ-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCθ is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.

Authors

Javier O. Valenzuela, Cristina Iclozan, Mohammad S. Hossain, Martin Prlic, Emily Hopewell, Crystina C. Bronk, Junmei Wang, Esteban Celis, Robert W. Engelman, Bruce R. Blazar, Michael J. Bevan, Edmund K. Waller, Xue-Zhong Yu, Amer A. Beg

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Figure 4

PKCθ is required for GVHD development in a B6→BALB/c BMT model.

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PKCθ is required for GVHD development in a B6→BALB/c BMT model.
2 × 106 ...
2 × 106 MACS-purified B6 WT, PKCθ–/–, or NF-κB p50–/–cRel–/– CD4+ and CD8+ donor T cells were injected i.v. into lethally irradiated (800–900 cGy) BALB/c recipient mice along with T cell–depleted BM (BM). Recipients were monitored 2–3 times weekly for clinical signs of GVHD and survival (A) and weight loss (B). Animals that were moribund were sacrificed and counted as GVHD mortality. H&E staining of the gut epithelium was performed approximately 20 days after T cell transfer (C). Original magnification, ×200. The initial proliferation and survival of donor CD8 T cells was measured by transferring CFSE-labeled cells and staining for CFSE+ CD8+ H-2b+ annexin V+ cells 4 days after transplantation (D). Donor T cell expansion was measured by staining for CD4+ H-2b+ and CD8+ H-2b+ cells in the spleen 4 days after transplantation (E). Horizontal bars indicate the averages of 4 mice in each group.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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