Autoimmunity in Vitiligo: IFN-γ–CXCL9/10 Axis and Tissue-Resident Memory T Cells (TRM)

Key Takeaways

IFN-γ induces keratinocyte/immune-cell secretion of CXCL9/10, recruiting CXCR3+ cytotoxic T cells that kill melanocytes.
CD8+ TRM persist in cleared skin and fuel relapse, explaining site-specific recurrence and Koebnerization.
JAK–STAT blockade (e.g., topical ruxolitinib) interrupts IFN-γ signaling; light therapy may suppress TRM activity.
Serum/lesional CXCL10 is a candidate biomarker of activity and response in some cohorts.

Abstract

Vitiligo is driven by cytotoxic immunity against melanocytes. Central to pathogenesis is an IFN-γ–dependent chemokine cascade (CXCL9/10) that recruits CXCR3+ T cells, while CD8+ tissue-resident memory T cells (TRM) sustain local immune tone and relapse after apparent clinical clearance. We summarize core experiments, human biopsy studies, biomarker signals, and how these mechanisms inform modern therapy (JAK inhibition, phototherapy, and combination strategies).

IFN-γ–CXCL9/10–CXCR3 Pathway

Table 1. Mechanistic cascade.

Step	Event	Notes
Trigger	Stress/antigen release from melanocytes	Oxidative stress, DAMPs
Amplification	IFN-γ production by T/NK cells	STAT1 activation in keratinocytes
Chemokines	CXCL9/10 upregulation	Gradients guide CXCR3+ CTLs
Effector	Melanocyte killing by CD8+ T cells	Perifollicular sparing explains islands

Tissue-Resident Memory T Cells (TRM)

TRM (CD69⁺ CD103⁺ CD8⁺) persist in cleared lesions and produce IFN-γ on restimulation.
Explain site-selective relapse and the Koebner phenomenon at trauma-prone sites.
Phototherapy may reduce TRM density/function; targeted JAK inhibition dampens their cytokine loop.

Table 2. TRM signals in human lesional skin.

Marker	Observation	Clinical correlate
CD69/CD103	Increased in lesional/perilesional skin	Relapse propensity
CXCR3 ligands	Elevated CXCL10 in tissue/serum	Activity biomarker candidate

Biomarkers of Activity

CXCL10 (serum/lesional) correlates with activity in several cohorts; declines with response to therapy in some studies.
Imaging + F-VASI/T-VASI remain clinical anchors; biomarker standardization is ongoing.

Therapeutic Implications

Topical JAK inhibitors (e.g., ruxolitinib) interrupt IFN-γ/STAT signaling, improving facial endpoints—see TRuE-V1/V2.
NB-UVB / Excimer 308 nm downregulate inflammatory chemokines and can mitigate TRM activity; synergy with topicals is common.
Maintenance: periodic light or topical immunomodulation may suppress TRM-driven relapse.

Limitations & Open Questions

Heterogeneity across cohorts; causality vs correlation for CXCL10 varies; long-term TRM dynamics under maintenance regimens require prospective trials.

References

Human and murine studies defining IFN-γ–CXCL9/10–CXCR3 axis in vitiligo pathogenesis.
Biopsy-based evidence of CD8+ TRM persistence in resolved lesions and links to relapse.
Phototherapy/JAK inhibition papers showing pathway modulation and clinical response.