PRR adjuvants restrain high stability peptides presentation on APCs

Reviewer #1 (Public Review):

Summary:

Li et al investigated how adjuvants such as MPLA and CpG influence antigen presentation at the level of the Antigen-presenting cell and MHCII : peptide interaction. They found that the use of MPLA or CpG influences the exogenous peptide repertoire presented by MHC II molecules. Additionally, their observations included the finding that peptides with low-stability peptide:MHC interactions yielded more robust CD4+ T cell responses in mice. These phenomena were illustrated specifically for 2 pattern recognition receptor activating adjuvants. This work represents a step forward for how adjuvants program CD4+ Th responses and provides further evidence regarding the expected mechanisms of PRR adjuvants in enhancing CD4+ T cell responses in the setting of vaccination.

Strengths:

The authors use a variety of systems to analyze this question. Initial observations were collected in an H pylori model of vaccination with a demonstration of immunodominance differences simply by adjuvant type, followed by analysis of MHC:peptide as well as proteomic analysis with comparison by adjuvant group. Their analysis returns to peptide immunization and analysis of strength of relative CD4+ T cell responses, through calculation of IC:50 values and strength of binding. This is a comprehensive work. The logical sequence of experiments makes sense and follows an unexpected observation through to trying to understand that process further with peptide immunization and its impact on Th responses. This work will premise further studies into the mechanisms of adjuvants on T cells

Weaknesses:

While MDP has a different manner of interaction as an adjuvant compared to CpG and MPLA, it is unclear why MDP has a different impact on peptide presentation and it should be further investigated, or at minimum highlighted in the discussion as an area that requires further investigation.

It is alluded by the authors that TLR activating adjuvants mediate selective, low affinity, exogenous peptide binding onto MHC class II molecules. However, this was not demonstrated to be related specifically to TLR binding. I wonder if some work with TLR deficient mice (TLR 4KO for example) could evaluate this phenomenon more specifically.

It is unclear to me if this observation is H pylori model/antigen-specific. It may have been nice to characterize the phenomenon with a different set of antigens as supplemental. Lastly, it is unclear if the peptide immunization experiment reveals a clear pattern related to high and low-stability peptides among the peptides analyzed.

Reviewer #2 (Public Review):

Adjuvants boost antigen-specific immune responses to vaccines. However, whether adjuvants modulate the epitope immunodominance and the mechanisms involved in adjuvant's effect on antigen processing and presentation are not fully characterized. In this manuscript, Li et al report that immunodominant epitopes recognized by antigen-specific T cells are altered by adjuvants.

Using MPLA, CpG, and MDP adjuvants and H. pylori antigens, the authors screened the dominant epitopes of Th1 responses in mice post-vaccination with different adjuvants and found that adjuvants altered antigen-specific CD4+ T cell immunodominant epitope hierarchy. They show that adjuvants, MPLA and CpG especially, modulate the peptide repertoires presented on the surface of APCs. Surprisingly, adjuvant favored the presentation of low-stability peptides rather than high-stability peptides by APCs. As a result, the low stability peptide presented in adjuvant groups elicits T cell response effectively.