Deficiency of protein kinase C-theta facilitates tolerance induction.
BACKGROUND
Protein kinase C-theta (PKCtheta) mediates critical T-cell receptor signals required for T-cell activation. We have recently shown that PKCtheta knockout (PKCtheta, H-2b) T cells, when transferred into T/B cell-deficient mice, failed to reject fully allogeneic (H-2d) cardiac grafts and that transgenic expression of antiapoptotic Bcl-xL gene in PKCtheta T cells restored allograft rejection.


METHODS
We used PKCtheta mice as recipients of cardiac allografts, compared with wild-type (WT) cardiac allograft transplantation. Anti-CD154 monoclonal antibody (MR1) and human CTLA4Ig were sued to induce donor-specific tolerance. T-cell proliferation, T-cell subsests, nuclear factor kappa B (NF-kappaB) activation, and Bax and Bcl-xL were analyzed.


RESULTS
Although suboptimal anti-CD154 monoclonal antibody or human CTLA4Ig failed to delay cardiac allograft rejection in WT mice, the same therapy induced long-term survival of cardiac allografts in PKCtheta mice. Donor-type second cardiac allografts (H-2d) were accepted, and third-party heart allografts (H-2k) were rejected by tolerant PKCtheta mice. However, tolerance state could not be effectively transferred with T cells from tolerance PKCtheta mice. Compared with WT mice, reduced NF-kappaB activation, T-cell proliferation, and T-cell infiltration in PKCtheta spleens were observed. PKCtheta mice reveal reduced CD4/CD25/FoxP3, Th1/Th17 subsets, and mouse MHC class II (IE)-reactive CD4Vbeta11 T cells. Apoptotic molecule, Bax, was increased and antiapoptotic molecule, Bcl-xL, was reduced in PKCtheta spleen cells.


CONCLUSIONS
We concluded that PKCtheta mice have a defected alloimmune response and are susceptible to tolerance induction, which is associated with a clonal deletion of T-cell subsets.
Wang
Lei
L
Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, USA.
Xiang
Zhidan
Z
Ma
Lian-Li
LL
Chen
Zhongyi
Z
Gao
Xiudan
X
Sun
Zuoming
Z
Williams
Phillip
P
Chari
Ravi S
RS
Yin
Deng-Ping
DP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D060908:CTLA-4 Antigen; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007527:Isoenzymes / Q000172:deficiency*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency*; D000074121:Protein Kinase C-theta; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D007527:Isoenzymes; D023201:CD40 Ligand; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta