cells among half of the cohort, which would be expected for a common unifying origin.Differential gene expression analysis revealed T cells with shared TCRs to be enriched for central memory markers, including CD69, SELL (CD62L) and the Th2-skewing transcription factor JunB (Figure 1b). By contrast, T cells with unique TCRs were more Th1 polarized, as reflected by their expression of STAT1, CX3CR1, GNLY, LGALS1, S100A9 and S100A10. Module scores using well-defined gene sets for Th1, Th2 and central memory phenotypes supported this transcriptional dichotomy (Figure 1c). In addition, protein expression measured by AbSeq revealed that shared TCRs were chronically antigen experienced with an amplified expression of LAG3 and TIM3, 5 which are enriched among cutaneous neoplastic T cells and promote tumorigenesis (Figure 1d). These findings collectively demonstrate that TCR usage phenotypically segregates S ezary cells based on distinct origins in their pathogenesis.Immune dysregulation induced by staphylococcal toxins has been reported to drive the Th2 cytokine production that is characteristic of SS. 2,4 We found that this phenotype was reproduced among S ezary cells with a shared toxinresponsive TCR, supporting the hypothesis that infectious agents influence this neoplastic process. On the other hand, these findings may also reflect inherent VDJ recombination biases that occur during thymocyte development, as TRBV20-1*01 and other staphylococcal toxin-responsive TCRs have been reported to be preferentially utilized by T cells among healthy individuals as well as patients with CTCL. 6 The presence of a Th2 profile among malignant cells could represent one carcinogenic pathway whereby the nuclear accumulation of the NLRP3 inflammasome promotes a positive Th2 feedback loop that bolsters cellular proliferation and resistance to apoptosis. 7 Interestingly, antibodymediated blockade of programmed death-1 enriched among S ezary cells blunts Th2 cytokine production but reciprocally and paradoxically unleashes their proliferation potential, 8 suggesting the Th2 cytokine profile may be a by-product rather than a primary instigator of disease progression.The high frequency of the Th2 cytokine profile observed among patients with SS may reflect the ubiquitous nature by which S. aureus is recovered from patients with CTCL. CTCL affects an older population with a naturally impaired skin barrier that fosters S. aureus overgrowth. Nevertheless, other factors also contribute to the pathogenesis of CTCL, as S. aureus is only identified in a subset of patients, and the contextual role of S. aureus as a natural commensal or pathogenic strain is difficult to dissociate. If S. aureus promotes the classic Th2 phenotype, these findings may help identify patients who respond to targeted Th2 depletion with the anti-CCR4 therapy mogamulizumab. Future studies aimed at unravelling the role of S. aureus in instigating CTCL may be pivotal for developing targeted therapies.

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