High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata
Annemieke de Jong, … , Raphael Clynes, Angela M. Christiano
Annemieke de Jong, … , Raphael Clynes, Angela M. Christiano
Published October 4, 2018
Citation Information: JCI Insight. 2018;3(19):e121949. https://doi.org/10.1172/jci.insight.121949.
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Research Article Dermatology

High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata

Abstract

Alopecia areata (AA) is an autoimmune disease in which cytotoxic T cells specifically target growing hair follicles. We used high-throughput TCR sequencing in the C3H/HeJ mouse model of AA and in human AA patients to gain insight into pathogenic T cell populations and their dynamics, which revealed clonal CD8+ T cell expansions in lesional skin. In the C3H/HeJ model, we observed interindividual sharing of TCRβ chain protein sequences, which strongly supports a model of antigenic drive in AA. The overlap between the lesional TCR repertoire and a population of CD8+NKG2D+ T cells in skin-draining lymph nodes identified this subset as pathogenic effectors. In AA patients, treatment with the oral JAK inhibitor tofacitinib resulted in a decrease in clonally expanded CD8+ T cells in the scalp but also revealed that many expanded lesional T cell clones do not completely disappear from either skin or blood during treatment with tofacitinib, which may explain in part the relapse of disease after stopping treatment.

Authors

Annemieke de Jong, Ali Jabbari, Zhenpeng Dai, Luzhou Xing, Dustin Lee, Mei Mei Li, Madeleine Duvic, Maria Hordinsky, David A. Norris, Vera Price, Julian Mackay-Wiggan, Raphael Clynes, Angela M. Christiano

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Figure 1

Expanded clones in affected skin are predominantly NKG2D+CD8+ T cells.

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Expanded clones in affected skin are predominantly NKG2D+CD8+ T cells. S...
Skin-draining lymph node cells from a C3H/HeJ mouse with graft-induced AA were sorted by flow cytometry into CD8+NKG2D– and CD8+NKG2D+ fractions. TCRβ chains of the sorted CD8+ T cell fractions as well as from the affected skin were sequenced by high-throughput sequencing. TCRβ sequences that represented >0.1% of the sequences in the affected skin and the frequencies of these sequences in the lymph node subsets are depicted as heatmaps (A). Skin-draining lymph node cells from a C3H/HeJ mouse with spontaneous AA were sorted into total CD4+ T cells, CD8+NKG2ACE–NKG2D–, CD8+NKG2ACE+NKG2D–, and CD8+NKG2ACE+NKG2D+. TCRβ chains of the sorted T cell fractions as well as 3 lesional skin sites (a, b, c, nonadjacent) were sequenced by high-throughput sequencing. TCRβ sequences that represented >0.1% of the sequences in the affected skin sites and the frequencies of these sequences in the lymph node subsets are depicted as heatmaps (B). Overlap between TCRβ sequences from the CD8+ T cell populations from skin-draining lymph nodes are depicted in a Venn diagram (C).