Experimental validation of the RATE tool for inferring HLA restrictions of T cell epitopes

Abstract

BackgroundThe RATE tool was recently developed to computationally infer the HLA restriction of given epitopes from immune response data of HLA typed subjects without additional cumbersome experimentation.ResultsHere, RATE was validated using experimentally defined restriction data from a set of 191 tuberculosis-derived epitopes and 63 healthy individuals with MTB infection from the Western Cape Region of South Africa. Using this experimental dataset, the parameters utilized by the RATE tool to infer restriction were optimized, which included relative frequency (RF) of the subjects responding to a given epitope and expressing a given allele as compared to the general test population and the associated p-value in a Fisher’s exact test. We also examined the potential for further optimization based on the predicted binding affinity of epitopes to potential restricting HLA alleles, and the absolute number of individuals expressing a given allele and responding to the specific epitope. Different statistical measures, including Matthew’s correlation coefficient, accuracy, sensitivity and specificity were used to evaluate performance of RATE as a function of these criteria. Based on our results we recommend selection of HLA restrictions with cutoffs of p-value < 0.01 and RF ≥ 1.3. The usefulness of the tool was demonstrated by inferring new HLA restrictions for epitope sets where restrictions could not be experimentally determined due to lack of necessary cell lines and for an additional data set related to recognition of pollen derived epitopes from allergic patients.ConclusionsExperimental data sets were used to validate RATE tool and the parameters used by the RATE tool to infer restriction were optimized. New HLA restrictions were identified using the optimized RATE tool.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-017-0204-1) contains supplementary material, which is available to authorized users.

Allergen and Epitope Targets of Mouse-Specific T Cell Responses in Allergy and Asthma

“…HLA types of all donors included in this study were determined by HLA typing (Table S5 in Supplementary Material). A genetic inference method, named restrictor analysis tool for epitopes (RATE) ( 25 ), was used to infer HLA restriction of epitopes from T cell response data in HLA typed subjects. While the inferred restrictions here are based on a limited set of donors ( n = 22), nevertheless it appears that all four HLA class II loci (DRB1; DRB3, DQ, and DP) appear to be restricting responses (Table 2 ).…”

“…HLA typing for Class I (HLA-A; HLA-B; HLA-C) and Class II (HLA-DQA1; HLA-DQB1, HLA-DRB1,3,4,5; HLA-DPB1) was performed by an ASHI-accredited (American society for histocompatibility and immunogenetics) laboratory at Murdoch University (Western Australia) as previously described ( 24 ). Potential HLA-epitope restriction odds ratios and relative frequencies were calculated using the RATE program ( 25 ). To further filter identified inferred restrictions, HLA class II binding predictions were performed for peptide restrictions inferred by the RATE program, as recommended by the IEDB ( 19 ).…”

Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

“…Specifically, RF = [(rsqrt(r)]/t, where r is the total number of responding donors and t is the total number of donors tested (2). The RF score has been calculated using RATE tool (39,40). HLA class II binding predictions were performed following two different strategies: one using NetMHCIIpan 3.2 21…”

CD4 T Cell Determinants in West Nile Virus Disease and Asymptomatic Infection

“…A Spearman correlation coefficient was calculated for evaluation of two-by-two correlations. The strength of associations between expression of a specific allele and detection of a positive epitope response was calculated as described previously (55,56). Briefly, odds ratios (ORs) were calculated, according to the following formula: OR = (A+R+)x(A−R−) (A−R+)x(A+R−) .…”

“…Briefly, odds ratios (ORs) were calculated, according to the following formula: OR = (A+R+)x(A−R−) (A−R+)x(A+R−) . A+R+ = number of subjects who expressed the specific allele and had a positive response to the specific peptide, A+R− = number of subjects who expressed the specific allele but did not have a positive response to the specific peptide, A−R+ = number of subjects who did not express the specific allele but had a positive response to the specific peptide, A−R− = number of subjects who did not express the specific allele and did not have a positive response to the specific peptide (56). Fisher's exact test was applied to calculate the statistical significance of the association between one or more specific HLA alleles and the response to a specific peptide (55).…”