Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
Immunodominance is a process in which the immune response focuses on one
or a few of all potential epitopes that exists within an antigen. The
mechanisms for immunodominance have not yet been determined. The work
described in this thesis has addressed the question whether competition
between peptides for presentation at the cell surface or competition
between Tcells for activation by the antigen presenting cell are
important mechanism for immunodominance. In an experimental model with
transplantation antigens there is no detectable difference in the amount
of subdominant epitopes presented at the cell surface in the presence or
absence of immunodominant epitopes. In a model with synthetic peptides
there is no correlation between peptide affinities for MHC class I or
T-cell avidity and immunodominance. These results indicate that
competition between epitopes for presentation at the cell surface is not
a determining mechanism in these models. We show that the antigens need
to be presented by the same cell for immunodominance to occur. We also
show that immunodominance is not absolute, since mice previously
inoculated with the complete antigenic barrier not only retain their
capacity to respond to subdominant epitopes but they are more easily
primed against subdominant epitopes indicating a passive mechanism for
immunodominance that allows some printing also against subdominant
epitopes.
Finally, we can overcome immunodominance in both of these models by
inoculation of high numbers of antigen bearing dendritic cells. Based on
these results we suggest that the determining mechanism for
immunodominance in these models is T-cell competition. T-cells may
compete for cytokines such as IL-12, access to the APC itself for
costimulation or any other factor provided by the APC. The second part of
this thesis concerns the role for interleukin-12 in the immune response
against tumors and for the initiation of primary and memory CTL responses
against synthetic peptide antigens. IL-12 is an important cytokine that
promotes cellular immunity mainly by the induction of interferon-gamma
production. IL-12 also augments the cytotoxic ability of both natural
killer cells and cytotoxic T-lymphocytes. We have shown that IL-12 is
important for the generation of innate immune responses against a TAP
deficient lymphoma (RMA-S) as well as adoptive immunity against the TAP
expressing lymphoma (RMA). We also show that IL-12 is important for the
generation of CTL responses against synthetic peptides pulsed on
dendritic cells. The need for IL-12 can be circumvented by immunization
with peptides together with adjuvant. Interestingly, IL-12 seems to be
important for the initiation of CTL memory responses also in mice
immunized with adjuvant. Once a memory response has been established
IL-12 is no longer needed for maintenance of that response