IMMUNODOMINANCE IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I–RESTRICTED T LYMPHOCYTE RESPONSES

Abstract

▪ Abstract Of the many thousands of peptides encoded by a complex foreign antigen that can potentially be presented to CD8+ T cells (T CD8+), only a small fraction induce measurable responses in association with any given major histocompatibility complex class I allele. To design vaccines that elicit optimal T CD8+responses, a thorough understanding of this phenomenon, known as immunodominance, is imperative. Here we review recent progress in unraveling the molecular and cellular basis for immunodominance. Of foremost importance is peptide binding to class I molecules; only ∼1/200 of potential determinants bind at greater than the threshold affinity (K d> 500 nM) associated with immunogenicity. Limitations in the T CD8+repertoire render approximately half of these peptides nonimmunogenic, and inefficient antigen processing further thins the ranks by approximately four fifths. As a result, only ∼1/2000 of the peptides in a foreign antigen expressed by an appropriate antigen presenting cell achieve immunodominant status with a given class I allele. A roughly equal fraction of peptides have subdominant status, i.e. they induce weak-to-nondetectable primary T CD8+responses in the context of their natural antigen. Subdominant determinants may be expressed at or above levels of immunodominant determinants, at least on antigen presenting cells in vitro. The immunogenicity of subdominant determinants is often limited by immunodomination: suppression mediated by T CD8+specific for immunodominant determinants. Immunodomination is a central feature of T CD8+responses, as it even occurs among clones responding to the same immunodominant determinant. Little is known about how immunodominant and subdominant determinants are distinguished by the T CD8+repertoire, or how (and why) immunodomination occurs, but new tools are available to address these questions.