Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients

Abstract

BackgroundTcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide.Methodology/Principal FindingsFrom 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN-γ, TNFα, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07–0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation.Conclusion/SignificanceThese results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy.

In silico Design of an Epitope-Based Vaccine Ensemble for Chagas Disease

“…We applied two methods to predict B cell epitopes: a structure-based approach and a sequence-based approach with the tool Bepipred2.0 (47). With the former, we identified a potential B cell epitope in the parasite KMP11 protein (Figure 1A), an antigen that has been thoroughly researched (63, 64). We identified a region of 15 residues long with all but one fulfilling the RSA threshold (RSA > 50%).…”

Trypanosoma cruzi vaccine candidate antigens Tc24 and TSA-1 recall memory immune response associated with HLA-A and -B supertypes in Chagasic chronic patients from Mexico

“…Additional CD8 + epitopes restricted to A02 alleles and derived from different antigens including cruzipain, FL-160, KMP-11, HSP-70, PFR1-4, and other trans-sialidases proteins have been identified in HLA-A*0201 Chagasic patients [ 26 , 27 , 41 , 43 – 46 ]. Our findings suggest the necessity to include a greater diversity of HLA supertypes in Chagas disease studies.…”

“…Thus, vaccine candidates should be tested in patients with a variety of HLA profiles, as shown by Lasso et al . (2016), who reported an epitope of KMP-11 protein that can be presented in the context of more than one HLA-I supertype (A02, A24 and A01) in Colombian Chagasic patients [ 27 ].…”

“…However, the extent of their recognition and processing by the human immune system and potential HLA restriction is still unclear. Most studies with Chagasic patients have focused on carriers of the A2 supertype, especially the HLA-A*0201 allele, due to its high frequency (about 45%) in Latin American populations [ 26 , 27 ] or with patients with unknown HLA.…”

A systematic review of the Trypanosoma cruzi genetic heterogeneity, host immune response and genetic factors as plausible drivers of chronic chagasic cardiomyopathy

“…Variations in HLA supertypes (such as HLA-A1, A2 and A24, which are present in CD8+ T cells where most of their epitopes are restricted to the HLA-A allele) have also been found to relate to disease pathology (Lasso et al ., 2016), with polymorphisms in HLA I and HLA II being reported to be associated with CCC (Deghaide et al ., 1998). Of the HLA I genes, it was shown that variations in HLAC*03 have a strong association with CCC compared with asymptomatic patients.…”