The relationship between immunodominance, DM editing, and the kinetic stability of MHC class II:peptide complexes

Abstract

Immunodominance refers to the restricted antigen specificity of T cells detected in the immune response after immunization with complex antigens. Despite the presence of many potential peptide epitopes within these immunogens, the elicited T-cell response apparently focuses on a very limited number of peptides. Over the last two decades, a number of distinct explanations have been put forth to explain this very restricted specificity of T cells, many of which suggest that endosomal antigen processing restricts the array of peptides available to recruit CD4 T cells. In this review, we present evidence from our laboratory that suggest that immunodominance in CD4 T-cell responses is primarily due to an intrinsic property of the peptide:class II complexes. The intrinsic kinetic stability of peptide:class II complexes controls DM editing within the antigen-presenting cells and thus the initial epitope density on priming dendritic cells. Additionally, we hypothesize that peptides that possess high kinetic stability interactions with class II molecules display persistence at the cell surface over time and will more efficiently promote T-cell signaling and differentiation than competing, lower-stability peptides contained within the antigen. We discuss this model in the context of the existing data in the field of immunodominance.

A Quantitative Analysis of the Variables Affecting the Repertoire of T Cell Specificities Recognized after Vaccinia Virus Infection

“…These observations suggest that, in general, a binding affinity that is neither too high nor too low may be optimal for epitope recognition during infection. It has also been suggested that peptide stability correlates best with immunodominance (54,55,61). However, in our hands, peptide stability did not correlate significantly better with immunodominance than did equilibrium binding measurements.…”

Dominance and Diversity in the Primary Human CD4 T Cell Response to Replication-Competent Vaccinia Virus

“…In this setting, Ag abundance has been hypothesized to influence the magnitude of CD4 responses (68). In our data set, proteins that are present in purified virion preparations were recognized significantly more often than proteins that are not detected in virions.…”

“…CD4 immunodominance is noted in the MHC class II-restricted response to LACK in Leishmania-infected H-2 d mice (67). Several factors influence CD4 immunodominance, including HLA-DM, the susceptibility of epitope-flanking regions to proteolysis, trafficking of proteins to various membranous compartments, especially in the setting of intracellular Ag synthesis, and innate activation of APC (68). MHC allelic variation of course plays a role, but probably less so than for CD8 responses due to the greater promiscuity for peptide binding of MHC class II compared with MHC class I.…”

Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide – MHC class I complexes

“…The cofactor tapasin additionally edits the peptide repertoire that is loaded onto class I molecules in favor of those with slow dissociation kinetics [10]. This is a similar function to that described for DM in MHC class II loading [11].…”