One of the normal
functions of the Ii protein is to prevent MHC class II molecules
from presenting endogenously synthesized antigenic epitopes to
CD4+ Th cells. It does so by blocking the antigenic peptide
binding trough of MHC class II molecules at synthesis. The Ii
protein is only removed in a coordinated process tightly linked
to charging of class II molecules with epitopes derived from
phagocytosed extracellular antigens (figure on left). When MHC
class II molecules are synthesized in the absence of Ii, they
are able to acquire and present epitopes derived from
intracellularly synthesized proteins, similar to the ‘survey’
function of MHC class I molecules that present epitopes to
cytotoxic T cells. In the case of tumor cells, it has been shown
that they can effectively be forced to simultaneously present
tumor antigens to both CD4+ and CD8+ T cells by generating the
MHC class I+/II+/Ii- phenotype tumor cells (figure on right). A
number of studies have demonstrated that the generation of the
MHC class I+/II+/Ii- phenotype in tumor cells generates a potent
tumor cell vaccine to inhibit tumor growth both in prevention
and cure models.
Another
application of Ii suppression is as an adjunct to DNA vaccines.
In order to induce a DNA vaccine-specific CTL immune response,
the encoded antigen must be expressed and processed in the
cytoplasm and then presented to CD8+ CTL via MHC class I
molecules. By inhibition of the Ii protein it is possible to the
simultaneous have antigenic epitopes presented by both MHC class
II and I molecules and thus significantly amplify the
immunogenicity of DNA vaccines. This application has been
successfully demonstrated pre-clinically in an HIV gp120
vaccine. A five-fold enhancement of gp120 vaccine efficiency was
observed when the DNA vaccine and Ii suppression construct were
co-administrated comparing to the groups in which the DNA
vaccine was given alone.
