Identification of novel NK cell-mediated immunosurveillance function: immunogenicity regulation by monitoring antigen frequency
Computational analysis of total amino acid sequences indicate that select combinations that occur less frequently are correlated to increased immunogenicity in humans. Much evidence has been gathered in silico, but little is known about in vivo experimental validation. This concept can be applied to adjuvant research where increased immunogenicity is desirable and can aid in the potency and efficacy of vaccines. A rare peptide called 5mer4 was found to adjuvant influenza vaccines by increasing survival, humoral and cellular immune responses with a speculated NK cell mediated mechanism. Therefore we hypothesize that rare peptides are able to stimulate an increased immune response in comparison to common peptides through a NK-mediated fashion. The first aim of this study is to determine whether rare sequences are able to stimulate an increased immune response collectively in comparison to commonly occurring peptides. Mice vaccinated with rare, semi-common and common peptides indicate a trend of heightened cellular immune response from rare peptides. However, select rare peptide sequences based on high IFNγ responses do not always correlate directly to increased vaccine efficacy against H5N1-H05 influenza virus, indicating that additional immune parameters need to be taken into consideration. When compared against other adjuvants, 5mer4 performed better in both humoral and survival studies. Previous findings suggest NK cell involvement warranted the second aim of this thesis which is to further delineate the role of NK cells as rare peptide immune modulators. Macrophages were evaluated to determine the effect of peptide, but no increase in stimulation could be observed. NK cells incubated with rare peptides show increased levels of early activation marker CD69 in comparison to common peptides. Microscopy data indicates that rare, but not common peptides are able to bind to NK cells. Depletion of NK abrogated adjuvant activity of 5mer4 peptide, suggesting the necessary role of NK cells for adjuvant effect. Taken together, rare peptides have shown the ability to modulate the immune response through NK cell activation verifying our hypothesis. These findings can be extrapolated towards multiple fields such as anti-tumor therapies and can lead to the development of immunomodulators with high efficacy at a lower cost.
Immunology, Natural Killer cell
Patel A, Dong JC, Trost B, Richardson JS, Tohme S, Babiuk S, et al. Pentamers not found in the universal proteome can enhance antigen specific immune responses and adjuvant vaccines. PLoS One 2012;7(8):e43802.