Abstract
It is well known that infiltration of pathogenic T-cells plays an important role in psoriasis pathogenesis. However, the antigen specificity of these activated T-cells is relatively unknown. Previous studies using T-cell receptor polymerase chain reaction technology (TCR-PCR) have suggested there are expanded T-cell receptor (TCR) clones in psoriatic skin, suggesting a response to an unknown psoriatic antigen. Here we describe the results of high-throughput deep sequencing of the entire αβ- and γδ- TCR repertoire in normal healthy skin and psoriatic lesional and non-lesional skin. From this study, we were able to determine that there is a significant increase in the abundance of unique β- and γ- TCR sequences in psoriatic lesional skin compared to non-lesional and normal skin, and that the entire T-cell repertoire in psoriasis is polyclonal, with similar diversity to normal and non-lesional skin. Comparison of the αβ- and γδ- TCR repertoire in paired non-lesional and lesional samples showed many common clones within a patient, and these close were often equally abundant in non-lesional and lesional skin, again suggesting a diverse T-cell repertoire. Although there were similar (and low) amounts of shared β-chain sequences between different patient samples, there was significantly increased sequence sharing of the γ-chain in psoriatic skin from different individuals compared to those without psoriasis. This suggests that although the T-cell response in psoriasis is highly polyclonal, particular γδ- T-cell subsets may be associated with this disease. Overall, our findings present the feasibility of this technology to determine the entire αβ- and γδ- T-cell repertoire in skin, and that psoriasis contains polyclonal and diverse αβ- and γδ- T-cell populations.
Highlights
Psoriasis vulgaris is a chronic, inflammatory skin disease characterized by raised, red scaly plaques (Lowes et al, 2014)
Deep sequencing demonstrates diverse and highly polyclonal αβ- and γδ- T-cell repertoires in psoriatic lesional skin Deep sequencing identified an average of 2.7 × 103 unique TCRβCDR3 sequences in normal skin, 3.2 × 103 unique TCRβ-CDR3 in non-lesional skin, and an average of 10.9 × 103 unique TCRβ-CDR3 sequences in psoriatic lesional skin, a significant three-fold increase compared to both normal (p = 0.0127) and non-lesional (p = 0.0295) skin (Figure 1a)
In combination with a clear signal of increased numbers of T-cells in psoriatic tissue, this suggests that the increase in T-cells is not due to the clonal expansion of a limited number of disease specific T-cells but the infiltration of large and diverse numbers of both αβ- and γδ- T-cells responding to an immune signaling cascade
Summary
Psoriasis vulgaris (plaque psoriasis) is a chronic, inflammatory skin disease characterized by raised, red scaly plaques (Lowes et al, 2014). Despite the established role of T-cells in psoriasis pathogenesis, the potential auto-antigens eliciting disease or the antigen specificity of T-cells contributing to psoriasis are relatively unknown. Previous evaluation of TCR repertoire in psoriasis has shown preferential usage of particular β-chain variable gene segments (Chang et al, 1995; Menssen et al, 1995). In these studies, a small number of TCR sequences was obtained from a potentially vast underlying diversity of TCR sequences (Robins et al, 2009) and clonal expansion was determined only in the context of particular Vβ-chain usages. Recent advances in generation deep sequencing have enabled the quantitative sampling of a significantly larger enough fraction of the T-cell repertoire to make strong inferences regarding the diversity of the T-cell repertoire and measure the degree of oligoclonality based on individual clone lineages (Robins, 2013)
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