High throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in Alopecia Areata

Jong, A de; Jabbari, A; Dai, Z; Xing, L; Lee, D; Li, MM; Duvic, M; Hordinsky, M; Norris, D.; Price, V; Mackay-WIggan, J; Clynes, R; Christiano, A. M.

doi:10.21417/b7q639

Cited by 18 publications

(24 citation statements)

References 16 publications

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“…In concert with upregulation of both MHC class I and MHC class II molecules, our data suggest AA CD4 + and CD8 + T cells are clonotypically expanded, with extensive overlap of TCR sequences between different single-cell clusters (Figure 4). Notably, in the murine AA T cells, clonotypic overlap was seen predominantly in the C1 CD8 + CCR7 + , C2 IFN-γ-expressing, and C6 CD8 + CD103 + CTL clusters, in line with previous reports (33). The clonally expanded C6 cluster had the highest level of NKG2D (Klrk1) and demonstrated elevated JAK2/STAT5 and cytolytic gene sets ( Figure 3), paralleling evidence in prior murine and human AA of these putatively pathogenic pathways (4,5).…”

Section: Discussionsupporting

confidence: 86%

A transcriptomic map of murine and human alopecia areata

Borcherding¹,

Crotts²,

Ortolan³

et al. 2020

JCI Insight

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Section: Discussionsupporting

confidence: 86%

A transcriptomic map of murine and human alopecia areata

Borcherding¹,

Crotts²,

Ortolan³

et al. 2020

JCI Insight

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“…The development of alopecia areata is associated with the collapse of HF immune privilege which subsequently increases antigen presentation to surveying T cells that recognize HF epithelial and/or melanocyteassociated antigens as foreign, and mount autoimmune responses against HFs [93,[97][98][99][100]. There are ongoing investigations trying to identify the exact HF antigen and antigen-specific T cells involved in the onset of alopecia areata [99,101]. The autoimmune attack does not kill HFSCs specifically, but, instead, the lower transient portion of anagen HFs [97].…”

Section: Influx Of Auto-reacting T-cells Into Hfsc Niche Disrupts Haimentioning

confidence: 99%

Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration

et al. 2020

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Stem cell activity is subject to non-cell-autonomous regulation from the local microenvironment, or niche. In adaption to varying physiological conditions and the ever-changing external environment, the stem cell niche has evolved with multifunctionality that enables stem cells to detect these changes and to communicate with remote cells/tissues to tailor their activity for organismal needs. The cyclic growth of hair follicles is powered by hair follicle stem cells (HFSCs). Using HFSCs as a model, we categorize niche cells into 3 functional modules, including signaling, sensing and message-relaying. Signaling modules, such as dermal papilla cells, immune cells and adipocytes, regulate HFSC activity through short-range cell-cell contact or paracrine effects. Macrophages capacitate the HFSC niche to sense tissue injury and mechanical cues and adipocytes seem to modulate HFSC activity in response to systemic nutritional states. Sympathetic nerves implement the message-relaying function by transmitting external light signals through an ipRGC-SCN-sympathetic circuit to facilitate hair regeneration. Hair growth can be disrupted by niche pathology, e.g. dysfunction of dermal papilla cells in androgenetic alopecia and influx of auto-reacting T cells in alopecia areata and lichen planopilaris. Understanding the functions and pathological changes of the HFSC niche can provide new insight for the treatment of hair loss.

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“…Thus the important ongoing search for elusive autoantigens and specific autoreactive CD8 1 T cells in AA research [49][50][51] might well turn out to be less crucial in terms of effective therapeutic intervention in patients with AA than the protection and restoration of HF IP. 3 Instead, a more sustained therapeutic research focus on upregulating or administering HF IP ''guardians,'' such as a-MSH, calcitonin gene-related peptide, and VIP, 14,48 and on counteracting the potently IP collapsepromoting neuropeptide substance P 52,53 might generate more universally effective treatment and have a more direct benefit in future AA management.…”

Section: Do Autoantigen Responses Play a Primary Or Secondary Role Inmentioning

confidence: 99%

“…26 This was rapidly confirmed independently at the genomic level in a major genome-wide association study. 51 The subsequent finding that transfer of autologous CD56 1 NKG2D 1 cells suffices to transform a completely normal human HF into one that shows all the key signs of human AA 45 not only provided the first functional evidence of a key role of NKG2D 1 cells in human AA pathobiology but also strongly suggested that specific HF autoantigens are not indispensable for the development of AA lesions (Fig 1, A), thus further supporting the notion that autoantigens could play a secondary role in human AA, at least in many affected patients. The large amounts of IFN-g produced by the transferred CD8/NKG2D cells 45,74 are thought to induce a ''cytokine storm'' effect in healthy human scalp skin xenotransplants, which breaks down HF IP and initiates the cascade of alopecia-promoting events depicted in Fig 4, A and B.…”

Section: Humanized Mouse Models Of Aa As a Unique Resource For Illumimentioning

confidence: 99%

Frontiers in alopecia areata pathobiology research

Gilhar

Laufer-Britva

Keren

et al. 2019

Journal of Allergy and Clinical Immunology

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This current review explores selected and as yet insufficiently investigated frontiers in current alopecia areata (AA) pathobiology research, with an emphasis on potential ''new'' players in AA pathobiology that deserve more systematic exploration and therapeutic targeting. Indeed, new evidence suggests that CD8 1 T cells, which have long been thought to be the central players in AA pathobiology, are not the only drivers of disease. Instead, subsets of natural killer (NK) and so-called ''unconventional'' T cells (invariant NK T cells, gd T cells, classic NK cells, and type 1 innate lymphoid cells), all of which can produce large amounts of IFN-g, might also drive AA pathobiology independent of classical, autoantigen-dependent CD8 1 T-cell functions. Another important new frontier is the role of regulatory lymphocyte subsets, such as regulatory T cells, gd regulatory T cells, NKT10 cells, and perifollicular mast cells, in maintaining physiologic hair follicle immune privilege (IP); the extent to which these functions are defective in patients with AA; and how this IP-protective role could be restored therapeutically in patients with established AA. Broadening our AA research horizon along the lines suggested above promises not only to open the door to innovative and even more effective immunotherapy strategies for AA but will also likely be relevant for other autoimmune disorders in which pathobiology, ectopic MHC class I expression, and IP collapse play an important role.

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High throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in Alopecia Areata

Cited by 18 publications

References 16 publications

A transcriptomic map of murine and human alopecia areata

A transcriptomic map of murine and human alopecia areata

Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration

Frontiers in alopecia areata pathobiology research

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