Abstract
Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans.
Highlights
In any one individual, CD4+ and CD8+ T cell responses elicited by virus infection or vaccination focus on a relatively small number of epitopes [1]
Our research interests lie in development of the T cell component of human immunodeficiency virus type 1 (HIV-1) vaccines stimulating protective CD8+ T cell responses
The G1 epitope was previously reported to be immunodominant in BALB/c mice [26,35], but from HIVA induced hardly detectable responses (Figure 1B and D top)
Summary
CD4+ and CD8+ T cell responses elicited by virus infection or vaccination focus on a relatively small number of epitopes [1] This immunodomination results from an interplay of multiple factors, which on one hand determine the abundance of displayed peptide-loaded MHC determinants on the surface of APCs and, on the other hand, affect the numbers of naıve T cells and their capacity to efficiently compete for their cognate determinants and generate effector and memory CD8+ T cell populations [2,3,4,5,6]. A consequence of immunodominance is that potentially protective responses to a majority of virus-carried determinants might not be used to their full potential or at all by the host immune system. This issue is pertinent to the human immunodeficiency virus type 1 (HIV-1). Better understanding of the rules governing immunodominance may lead to novel rational strategies for induction of broader, more protective T cell responses against HIV-1 and other viruses
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