The existence of two types of proteasome, the constitutive proteasome and the immunoproteasome, may serve as another layer of protection against autoimmunity

Negative selection of CD8 single positive thymocytes is based on the presentation through the major histocompatibility complex (MHC) class I pathway of peptides derived from degradation of self-proteins by the constitutive proteasome and the immunoproteasome in the thymus. Then naïve CD8+ T-cells can be primed by mature dendritic cells. In mature dendritic cells peptides presented by MHC class I molecules are derived from degradation of endogenous self-proteins or through the process of cross-presentation from degradation of exogenous proteins by the immunoproteasome. In the absence of infection, peripheral cells display peptides on MHC class I molecules derived from degradation of endogenous self-proteins by the constitutive proteasome. The pool of peptides derived from protein degradation by the constitutive proteasome differs from the pool peptides derived from protein degradation by the immunoproteasome. Thus the probability of an autoreactive naïve CD8+ T-cell that escaped negative selection, and converted by a mature dendritic cell to autoreactive cytolytic T-cell, to kill a normal cell in the periphery, is reduced.