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EpiQuest-T: Antigenicity index and epitope's immunodominance

November 2, 2018

Epitopes for cytotoxic lymphocytes bind to MHC class I molecules, and, in the context of MHC, are specifically recognised by T-cell receptor. It is generally accepted that T-cell epitopes may be divided into strong, moderate and weak, depending on their ability to effectively trigger the CTL reaction against the target.

 

Thinking about the vaccine that includes individual CTL epitopes, one would like to have means to select only strong epitopes, as this defines the effectiveness of the response in a vaccine recipient: the presence of the weak epitopes may abolish the response altogether [1].

 

One of the key features of a strong epitope is a strong binding of the peptide to the groove of MHCI and, possibly, TCR. We have previously demonstrated that our program EpiQuest-T, based on peptide sequence analysis (see the previous blog), can discriminate strong epitopes from the weak and negative ones. However, as we have used the definitions of strong/weak epitopes as were assigned by IEDB, it was unclear what exactly defines those qualities of the epitope peptides.

 

The group of Prof. T. Elliott has previously developed several derivatives of the original mouse CTL epitope and demonstrated their different activity in ability to induce CTLs, likely related to the affinity of the peptides to MHCI [2,3]. We have analysed the AGI (antigenicity index) of these epitopes using EpiQuest-T software and compared the obtained data with the relative activity of the epitopes. The results clearly show a strong correlation between the activity of epitope and the AGI index (see Fig.1)

 

These results suggest the applicability of EpiQuest-T to analyse the relative “strength” of the preselected CTL epitopes and of their derivatives, obtained by point mutations of some the amino acids.

Fig.1. Immunodominance hierarchies of several related epitopes and their antigenicity index.

C57BL/6 mice were immunized by intramuscular injection with pDUO encoding the peptide variants indicated below. After 12 days, the number of SIINFEKL‐specific T cells induced was measured directly ex vivo by IFN‐γ ELISPOT. The results shown are combined from at least two separate experiments, with each data point representing an individual mouse. Horizontal bars depict group means. For the sequences of the peptides, the AGI indexes were determined using EpiQuest-T program and H2kB-specific matrix.It can be clearly seen that ability of a peptide epitope to induce CTL response correlates with the AGI index predicted by EpiQuest-T.

 

References:

[1] Chung, B., Stuge, T.B., Murad, J.P., Beilhack, G., Andersen, E., Armstrong, B.D., Weber, J.S., and Lee, P.P. (2014). Antigen-Specific Inhibition of High-Avidity T Cell Target Lysis by Low-Avidity T Cells via Trogocytosis. Cell Reports 8, 871–882.

 

[2] Howarth, M., Williams, A., Tolstrup, A.B., and Elliott, T. (2004). Tapasin enhances MHC class I peptide presentation according to peptide half-life. Proc Natl Acad Sci U S A 101, 11737–11742.

 

[3] Thirdborough, S.M., Roddick, J.S., Radcliffe, J.N., Howarth, M., Stevenson, F.K., and Elliott, T. (2008). Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide – MHC class I complexes. European Journal of Immunology 38, 364–369.

 

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