Deficiency of protein kinase C-theta facilitates tolerance induction.

Background. Protein kinase C-theta (PKCθ) mediates critical T-cell receptor signals required for T-cell activation. We have recently shown that PKCθ knockout (PKCθ -/- , 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 PKCθ -/- T cells restored allograft rejection. Methods. We used PKCθ -/- 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-κB) activation, and Bax and Bcl-x L 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 PKCθ -/- mice. Donor-type second cardiac allografts (H-2d) were accepted, and third-party heart allografts (H-2k) were rejected by tolerant PKCθ -/- mice. However, tolerance state could not be effectively transferred with T cells from tolerance PKCθ -/- mice. Compared with WT mice, reduced NF-κB activation, T-cell proliferation, and T-cell infiltration in PKCθ -/- spleens were observed. PKCθ -/- mice reveal reduced CD4 + /CD25 + /FoxP3 + , Thl/Thl7 subsets, and mouse MHC class II (IE)-reactive CD4+Vβ11 + T cells. Apoptotic molecule, Bax, was increased and antiapoptotic molecule, Bcl-x L , was reduced in PKCθ -/- spleen cells. Conclusion. We concluded that PKCθ -/- mice have a defected alloimmune response and are susceptible to tolerance induction, which is associated with a clonal deletion of T-cell subsets.