High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata
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
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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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 5

TCRβ analysis of lesional scalp and blood in AA patients, and response to treatment with oral tofacitinib.

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TCRβ analysis of lesional scalp and blood in AA patients, and response t...
TCRβ sequencing was performed on skin biopsies from normal scalp (n = 4), AA lesional scalp (patchy AA [AAP]) (n = 8), and alopecia totalis and alopecia universalis scalp (AT/AU) (n = 8). The clonality of the scalp T cell repertoire is indicated (A) and the number of expanded CD8+ T cell clones among the top 100 most abundant clones in the scalp is shown (B). *P < 0.05, 1-way ANOVA and Tukey’s honest significant difference. SALT scores from 8 AA patients that were treated with oral tofacitinib at baseline and at the time of last biopsy during treatment (t = 24 weeks in most patients), the lowest SALT score attained on treatment, and the highest SALT score in the 6 months following treatment cessation (C). At baseline and after 24 weeks (or more) of tofacitinib treatment the clonality of the scalp was determined (D) as well as the number of expanded CD8+ T cells among the top 100 most abundant scalp T cell clones. *P < 0.05, 2-tailed Student’s t test (E). The percentage of reads represented by the top 100 T cell clones in the lesional scalp at baseline (blue bars) and the percentage of reads represented by the same clones after treatment (red bars). The circles indicate the T cell clones that are still expanded after treatment and their coreceptor expression (white circle, CD4+; black circle, CD8+; gray circle, unknown) (F).