PKCtheta is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice. J Clin Invest 2009 Dec;119(12):3774-86
Date
11/13/2009Pubmed ID
19907075Pubmed Central ID
PMC2786796DOI
10.1172/JCI39692Scopus ID
2-s2.0-72849123229 (requires institutional sign-in at Scopus site) 66 CitationsAbstract
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 theta (PKCtheta), a key regulator of TCR signaling. In contrast, PKCtheta was required for alloreactivity and GVHD induction. Furthermore, absence of PKCtheta raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCtheta-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCtheta is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.
Author List
Valenzuela JO, Iclozan C, Hossain MS, Prlic M, Hopewell E, Bronk CC, Wang J, Celis E, Engelman RW, Blazar BR, Bevan MJ, Waller EK, Yu XZ, Beg AAAuthor
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Marrow Transplantation
Female
Graft vs Host Disease
Graft vs Leukemia Effect
In Vitro Techniques
Isoantigens
Isoenzymes
Leukemia, Experimental
Listeria monocytogenes
Lymphocyte Activation
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Transgenic
Ovalbumin
Peptide Fragments
Protein Kinase C
Protein Kinase C-theta
Retroviridae Infections
Signal Transduction
T-Lymphocytes
