Sources of diversity in T cell epitope discovery

Abstract

CD8-positive T cells respond to small antigenic peptide fragments presented on class I major histocompatibility complexes (MHCs). Those specific T cell epitopes capable of precipitating a cellular immune response are either derived from (altered) self (i.e. they are autoimmune- or cancer-associated) or come from foreign sources (i.e. they are pathogen-associated). Identification of T cell epitopes provides elementary information that can be employed in technologies that monitor and predict the likely outcome of an immune response, as well as in therapeutic and vaccine development efforts. The coexistence between host and pathogen has largely driven the diversification of both their systems of immune surveillance and their antigenic determinants, respectively. In this review, we discuss the multitude of factors that introduce diversity to the T cell response from both sides of the host-pathogen interaction. Furthermore, we provide an overview of a variety of commonly employed methods and tools to characterize class I MHC restricted antigen presentation and recent endeavors towards the harmonization of reporting data concerning T cell responses.

Defining CD8+ T Cell Determinants during Human Viral Infection in Populations of Asian Ethnicity

“…To date, however, few studies have addressed whether this also translates to an efficient prediction of relevant human CD8 + T cell determinants, in particular, for Asian populations. Our previous studies suggested that bioinformatics tools may be inefficient for the prediction of CD8 + T cell epitopes in the context of Asian populations (9). In this study, we further confirm our observations in two different experimental settings.…”

“…The lack of sufficient experimental data for these populations needed to adequately train the predictive algorithms is likely to contribute to this scenario (9). However, we do not exclude the possibility that algorithms could accurately predict epitopes that may have been missed by experimental screens.…”

“…Because most studies to date have focused on Caucasian populations, this information is largely available for the most frequently expressed Caucasian molecules (e.g., HLA-A*0201), although it is scarce or not present at all for many HLA class I alleles present in individuals of different ethnicities. This is the case for Asian populations for whom definitions of CD8 + T cell epitopes have thus far been limited (9). The NetMHCpan algorithm represents an important attempt to overcome the limited HLA coverage of predictive algorithms.…”

Stability Screening of Arrays of Major Histocompatibility Complexes on Combinatorially Encoded Flow Cytometry Beads

“…Using the encoded bead sets, the binding properties of MHC molecules can be determined for individual epitopes by measuring the stability of the complex through subunit-specific antibody staining as demonstrated for MHC variants of both human and murine origin. The exact contribution of amino 4 The abbreviations used are: pMHC, peptide-MHC; ␤2m, ␤2-microglobulin; HLA, human leukocyte antigens; J, 3-amino-3-(2-nitro)phenyl-propanoic acid residue; MES, 4-morpholineethanesulfonic acid; PB, Pacific Blue; PE, phycoerythrin. …”

“…Such efforts are confronted with both an overwhelming diversity of potentially immunogenic peptide sequences and the polymorphism of the MHC system whereby each allelic product has a distinct peptide-binding motif that dictates their interactions. This has led to the development of a myriad of assays to probe either the ability of peptide-MHC (pMHC) 4 molecules to stimulate a specific population of T cells or ascertain the specificity and affinity of the peptide for a particular MHC variant (1)(2)(3)(4). Cell-free biophysical methods that employ soluble complexes purified to homogeneity have the advantage of directly measuring the molecular interaction between the peptide and MHC without the confounding effects of simultaneous expression of multiple MHC variants in a cellular context.…”