Date Published: April 25, 2013
Publisher: Public Library of Science
Author(s): Leon C. W. Lin, Inge E. A. Flesch, David C. Tscharke, Christopher C. Norbury.
Immunodominance is a fundamental property of CD8+ T cell responses to viruses and vaccines. It had been observed that route of administration alters immunodominance after vaccinia virus (VACV) infection, but only a few epitopes were examined and no mechanism was provided. We re-visited this issue, examining a panel of 15 VACV epitopes and four routes, namely intradermal (i.d.), subcutaneous (s.c.), intraperitoneal (i.p.) and intravenous (i.v.) injection. We found that immunodominance is sharpened following peripheral routes of infection (i.d. and s.c.) compared with those that allow systemic virus dissemination (i.p. and i.v.). This increased immunodominance was demonstrated with native epitopes of VACV and with herpes simplex virus glycoprotein B when expressed from VACV. Responses to some subdominant epitopes were altered by as much as fourfold. Tracking of virus, examination of priming sites, and experiments restricting virus spread showed that priming of CD8+ T cells in the spleen was necessary, but not sufficient to broaden responses. Further, we directly demonstrated that immunodomination occurs more readily when priming is mainly in lymph nodes. Finally, we were able to reduce immunodominance after i.d., but not i.p. infection, using a VACV expressing the costimulators CD80 (B7-1) and CD86 (B7-2), which is notable because VACV-based vaccines incorporating these molecules are in clinical trials. Taken together, our data indicate that resources for CD8+ T cell priming are limiting in local draining lymph nodes, leading to greater immunodomination. Further, we provide evidence that costimulation can be a limiting factor that contributes to immunodomination. These results shed light on a possible mechanism of immunodomination and highlight the need to consider multiple epitopes across the spectrum of immunogenicities in studies aimed at understanding CD8+ T cell immunity to viruses.
Immunodominance is a term used to describe the preferential recognition of some epitopes over others in a complex antigen and is a fundamental property of all immune responses. CD8+ T cell responses to viruses are no exception and immunodominance has been noted for many viruses in mice and humans , . Immunodominance arises due to factors that affect either 1) the amount of peptide-MHC (pMHC) complexes, including abundance of parent antigen, ease of processing and affinity of peptides for MHC – or 2) the quantity or quality of T cells in the naive repertoire that recognize these pMHC complexes , , , , –. An additional determinant that emerges from the intersection of the factors above is immunodomination, which is the ability of T cells with dominant specificities to inhibit responses to less-dominant epitopes. This is observed most clearly in secondary infections, where some memory T cells are clearly less able to compete –. However, it must also operate in primary infection, because deletion of immunodominant epitopes allows responses to subdominant epitopes to increase , , . Further in some, but not all cases pre-priming of individual epitopes can lead to radically altered dominance hierarchies, presumably because the already primed T cells have an advantage over other specificities , , . Finally, competition amongst the various clones recognising the same specificity can be directly observed during infection by monitoring the expansion adoptively transferred TCR transgenic T cells compared with the endogenous polyclonal response . While the mechanism of immunodomination remains obscure, it can be relieved if the epitopes are presented on separate antigen presenting cells (APCs). Therefore it is most likely due to competition for resources either on APCs or released by APCs in the immediate environment, but these remain undefined , –.
Infection route has been suggested to alter several aspects of CD8+ T cell responses to a variety of viruses including priming mechanism, magnitude and quality –. Here we demonstrate clearly that for VACV, immunodominance also needs to be considered. This leads to the first important conclusion of this work, which is that where magnitude of response is a primary read-out, examining responses to a single epitope can be misleading. For example, if B820 was used as a sole epitope in the experiment shown in Figure 1A, one would conclude that i.d. or s.c. injections of VACV were most immunogenic. In contrast if the majority of the SDE were chosen, the opposite conclusion would be drawn. The size of differences in response for individual SDE varied, but were up to four-fold for C4125 across the routes. Analyzing the total number of epitope-specific CD8+ T cells removes the apparent improvement of B820-specific response seen by the peripheral routes, but makes the suppressive effect of these routes on the SDE more pronounced, with the difference for C4125 being more than seven-fold. So while as an overall picture, the change in dominance profile across the doses seems quite modest compared with the very big differences in virus spread and number of priming sites, effects were substantial for some individual epitopes. Much VACV immunology in the past has used recombinant viruses and responses to a single foreign epitope were monitored. In the light of our results some conclusions from these earlier experiments may need to be reconsidered. Indeed the experiments shown here with HSVgB498 demonstrate that different forms of antigen can change the dominance ranking of an epitope dramatically in the context of a recombinant VACV. This in turn alters its competitiveness as an immunogen differentially according to route. There are also lessons here for studies of immunodominance using other viruses where few epitopes are known or used.