PKCtheta is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice.
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.
Valenzuela
Javier O
JO
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Iclozan
Cristina
C
Hossain
Mohammad S
MS
Prlic
Martin
M
Hopewell
Emily
E
Bronk
Crystina C
CC
Wang
Junmei
J
Celis
Esteban
E
Engelman
Robert W
RW
Blazar
Bruce R
BR
Bevan
Michael J
MJ
Waller
Edmund K
EK
Yu
Xue-Zhong
XZ
Beg
Amer A
AA
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
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