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

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

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graftversus-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.

Original languageEnglish (US)
Pages (from-to)3774-3786
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number12
DOIs
StatePublished - Dec 1 2009

ASJC Scopus subject areas

  • Medicine(all)

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    Valenzuela, J. O., Iclozan, C., Hossain, M. S., Prlic, M., Hopewell, E., Bronk, C. C., Wang, J., Celis, E., Engelman, R. W., Blazar, B. R., Bevan, M. J., Waller, E. K., Yu, X. Z., & Beg, A. A. (2009). PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice. Journal of Clinical Investigation, 119(12), 3774-3786. https://doi.org/10.1172/JCI39692