Self-Peptidome Variation Shapes Individual Immune Responses

Abstract

The relationship between human genetic variation and disease has not been fully elucidated. According to the present view on infectious diseases pathogen resistance is linked to human leukocyte antigen (HLA) class I/II variants and their individual capacity to present pathogen-derived peptides. Yet, T cell education in the thymus occurs through negative and positive selection, and both processes are controlled by a combination of HLA class I/II variants and peptides from the self. Therefore, the capacity of given HLA class I/II variants to bind pathogen-derived peptides is only one part of the selective process to generate effective immune responses. We thus propose that peptidome variation contributes to shaping T cell receptor (TCR) repertoires and hence individual immune responses, and that this variation represents inherent modulator epitopes.

Keywords: HLA; T cell receptor; disease; immune responses; inherent modulator epitopes; peptide.

Figure 1

T Cell Selection Depends on the Affinity of Its TCR to Self Peptide-HLA Class I/II Complexes. If TCR affinity is low (orange), T cells are eliminated by positive selection. If TCR affinity is too high, T cells are eliminated by negative selection (blue). All others T cells are selected (green). Abbreviations: HLA, human leukocyte antigen; TCR, T cell receptor.

Figure 2

Key Figure. Impact of Self Peptidome Variation on the Generation of T Cell Repertoires for the Same HLA Class I/II Variants. A self-peptidome variation can impact the binding of a peptide to the HLA class I/II variants of a given individual. This change will affect the affinity of TCRs for the HLA-peptide complex (peptide variant 1 and 2) and hence directly impact TCR repertoires. Moreover, self-peptidome variation could also generate a peptide that cannot be presented so it will not be part of the immune-peptidome, and that will also impact TCR repertoires (peptide variant 3). Abbreviations: HLA, human leukocyte antigen; TCR, T cell receptor.