title: PKCtheta is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice.
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 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.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Javier O
authors.initials: JO
authors.lastname: Valenzuela
authors.forename: Cristina
authors.initials: C
authors.lastname: Iclozan
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.forename: Martin
authors.initials: M
authors.lastname: Prlic
authors.forename: Emily
authors.initials: E
authors.lastname: Hopewell
authors.forename: Crystina C
authors.initials: CC
authors.lastname: Bronk
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Robert W
authors.initials: RW
authors.lastname: Engelman
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bevan
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000201:enzymology* / Q000209:etiology / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology / Q000502:physiology*; D066298:In Vitro Techniques; D007519:Isoantigens; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007942:Leukemia, Experimental / Q000201:enzymology* / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000074121:Protein Kinase C-theta; D012192:Retroviridae Infections / Q000201:enzymology* / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D007519:Isoantigens; D007527:Isoenzymes; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta