Abstract
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.
Highlights
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
Peripheral routes of infection sharpen immunodominance To extend published results suggesting an effect of vaccination route on CD8+ T cell immunodominance, groups of C57BL/6 mice were infected with 16106 plaque forming units vaccinia virus Western Reserve (WR) strain by i.p., i.d., intravenous (i.v.) and subcutaneous (s.c.) injection
Responses in mice infected by the two peripheral routes (i.d. and s.c.) had identical immunodominant epitope (IDE):sub-dominant epitopes (SDE) ratios of around 50%, but use of the systemic i.p. and to a slightly greater extent i.v. route reduced the dominance of B820 to around 30%
Summary
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. 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 [30,31,32,33,34]. It must operate in primary infection, because deletion of immunodominant epitopes allows responses to subdominant epitopes to increase [10,30,35]. It is most likely due to competition for resources either on APCs or released by APCs in the immediate environment, but these remain undefined [36,38,39,40]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
