Deficiency of protein kinase C-theta facilitates tolerance induction.
TRANSPLANTATION(2009)
摘要
Background. Protein kinase C-theta (PKC theta) mediates critical T-cell receptor signals required for T-cell activation. We have recently shown that PKC theta knockout (PKC theta(-/-), 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-x(L) gene in PKC theta(-/-) T cells restored allograft rejection. Methods. We used PKC theta(-/-) mice as recipients of cardiac allografts, compared with wild-type (WT) cardiac allograft transplantation. Anti-CD154 monoclonal antibody (MR1) and human CTLA41g were sued to induce donor-specific tolerance. T-cell proliferation, T-cell subsests, nuclear factor kappa B (NF-kappa B) activation, and Bax and Bcl-x(L) were analyzed. Results, Although suboptimal anti-CD 154 monoclonal antibody or human CTLA41g failed to delay cardiac allograft rejection in WT mice, the same therapy induced long-term survival of cardiac allografts in PKC theta(-/-) mice. Donor-type second cardiac allografts (H-2d) were accepted, and third-party heart allografts (H-2k) were rejected by tolerant PKC theta(-/-) mice. However, tolerance state could not be effectively transferred with T cells from tolerance PKC theta(-/-) mice. Compared with WT mice, reduced NF-kappa B activation, T-cell proliferation, and T-cell infiltration in PKC theta(-/-) spleens were observed. PKC theta(-/-) mice reveal reduced CD4(+)/CD25(+)/FoxP3(+), Th1/Th17 Subsets, and mouse MHC class II (IE)-reactive CD4(+)V beta 11(+) T cells. Apoptotic molecule, Bax, was increased and antiapoptotic molecule, Bcl-x(L), was reduced in PKC theta(-/-) spleen cells. Conclusion. We concluded that PKC theta(-/-) mice have a defected alloimmune response and are susceptible to tolerance induction, which is associated with a clonal deletion of T-cell Subsets.
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关键词
PKC-theta,Costimulation,Allograft,Tolerance
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