Deficiency of protein kinase C-theta facilitates tolerance induction

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.

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.

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.

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.