Clonally Expanded CD8+ T Cells May Play Role in Alopecia Areata

New research is helping to elucidate the role of clonally expanded CD8+ T cells in the development of alopecia areata (AA). The authors of the new study, which was published in Cell Reports, say their findings could have important implications for the monitoring and treatment of the disease.¹

Corresponding author Angela M. Christiano, PhD, of Columbia University, and colleagues, noted that the pathogenesis of AA is complex and multifactorial. One of the most significant factors, though, is cytotoxic CD8+ T cells, which they said act as key drivers of disease progression.

The finding that expanded CD8+ T-cell clones have a causal role in AA could lead to significant developments in the treatment of AA, the authors wrote. | Image credit: Nadya Kolobova - stock.adobe.coma

“They not only mediate epithelial cell death and subsequent HR (hair follicle) regression, but also perpetuate immune cell infiltration by releasing inflammatory cytokines into the surrounding HF microenvironment,” they wrote.

Previous work by Christiano and colleagues showed that the above process is facilitated by interferon-γ (IFN-γ) and members of the γ chain cytokine family and mediated through Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling.²

That work helped lead to the approval of JAK inhibitors as a treatment for AA, the authors noted. Still, many patients experience disease recurrence after discontinuing treatment. When that happens, patients have few therapeutic options.¹

In hopes of expanding those options, the investigators decided to focus on the role of CD8+ T cells in the disease. They noted that CD8+ T cells have been found to play a key role in the disease. Their clonality has been positively correlated with disease severity and also inversely correlated with sensitivity to the JAK inhibitor tofacitinib (Xeljanz; Pfizer).³ 

“Nevertheless, the kinetics of CD8+ T cell clonality and its relationship to time-dependent changes in transcriptional profiles and cell states remain unanswered questions,” Christiano and colleagues said.¹ In addition, they said it remains unclear whether expanded CD8+ T cell clones are a cause of AA pathogenesis itself.

The investigators conducted single-cell RNA and T-cell receptor (TCR) sequencing on a mouse model of AA. They analyzed skin-derived T cells and skin-draining lymph nodes—the presumed site of antigen-mediated T-cell priming—and found a major expansion of T-cell clones associated with disease onset.

“Here, we observed the emergence of hyperexpanded clones in the skin during active disease (weeks 8-16 post skin graft, marked by rapidly progressing hair loss) and their return to baseline during the chronic stages of disease (weeks 20 to 24, when mice exhibit total-body hair loss),” they explained.

They next engineered TCR retrogenic mice and genetically engineered T cells to see whether expanded CD8+ T-clones clones were sufficient to spark AA. They found that it was.

The finding that expanded CD8+ T-cell clones have a causal role in AA could lead to significant developments in the treatment of AA, the authors said. They noted that sequencing technologies could be used to track expanded TCR sequences and therefore act as a biomarker for disease progression, prognosis, and treatment response. They said the fact that expanded T-cell clones are present in both the blood and the scalp of patients with AA should help make such a strategy feasible.

The investigators added that expanded clones, including tissue-resident memory T cells, persist during chronic AA. That suggests they may play a role in disease relapse. They said therapeutic strategies that can eliminate pathogenic clones might also address the persistence of tissue-resident memory T cells and therefore limit recurrence.

References

1. Dai Z, Chang Y, Lee EY, et al. Single-cell analysis of temporal immune cell dynamics in alopecia areata reveals a causal role for clonally expanded CD8+ T cells in disease. Cell Rep. 2025;44(7):115798. doi:10.1016/j.celrep.2025.115798

2. Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043-1049. doi:10.1038/nm.3645

3. de Jong A, Jabbari A, Dai Z, et al. High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata. JCI Insight. 2018;3(19):e121949. doi:10.1172/jci.insight.121949