HLA class I allele promiscuity revisited

Abstract

The peptide repertoire presented on human leukocyte antigen (HLA) class I molecules is largely determined by the structure of the peptide binding groove. It is expected that the molecules having similar grooves (i.e., belonging to the same supertype) might present similar/overlapping peptides. However, the extent of promiscuity among HLA class I ligands remains controversial: while in many studies T cell responses are detected against epitopes presented by alternative molecules across HLA class I supertypes and loci, peptide elution studies report minute overlaps between the peptide repertoires of even related HLA molecules. To get more insight into the promiscuous peptide binding by HLA molecules, we analyzed the HLA peptide binding data from the large epitope repository, Immune Epitope Database (IEDB), and further performed in silico analysis to estimate the promiscuity at the population level. Both analyses suggest that an unexpectedly large fraction of HLA ligands (> 50%) bind two or more HLA molecules, often across supertype or even loci. These results suggest that different HLA class I molecules can nevertheless present largely overlapping peptide sets, and that "functional" HLA polymorphism on individual and population level is probably much lower than previously anticipated.

Fig. 1

Distribution of predicted HLA class I ligands of viral origin. All predicted ligands of the 20 most frequent HLA-A and HLA-B molecules in US subpopulations of a certain ethnic background (European, African, Asian and Hispanic) were classified into three categories: unique ligands (exclusively presented by one HLA class I molecule), within-supertype promiscuous ligands (exclusively targeted by one HLA supertype, but presented by at least two class I HLA molecules within this supertype) and across-supertype promiscuous ligands (targeted by HLA molecules belonging to at least two different HLA supertypes)

Fig. 2

Correlation between the predicted fraction of unique ligands for HLA-B molecules and mean set point viral load associated with the same molecule or the relative hazard (RH).The fraction of uniquely presented HIV-1 peptides for an allele was calculated by comparing the predicted HIV-1 peptides for a particular allele with all the predicted HIV-1 peptides for the most frequent HLA alleles (top 20 HLA-A and HLA-B as listed in Table S4) in the Caucasian population. The predictions were performed with NetMHCpan (Hoof et al. 2009) to obtain data for as many as possible alleles. The correlation between the fraction of unique ligands and a mean set point viral load per HLA molecule taken from Fellay et al. (2009) and b RH taken from Gao et al. (2001) are shown. For (b), whenever available we have used allele specific RH; in other cases, we used the fraction of HIV-1 peptides estimated for the most dominant HLA-B allele to correlate with the relative hazard assigned to two digit HLA-B identifier (e.g., the relative hazard associated with B*40 is correlated with the fraction of unique HIV-1 peptides presented by HLA-B*4001). The Spearman correlation coefficients and corresponding significance values are reported in each figure. The data used to generate these graphs are given in Table S5