T-cell competition as a mechanism for immunodominance and the role for IL-12 in CTL responses

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.