Research Scientist University of Iowa Iowa city, Iowa, United States
Introduction/Rationale: Alopecia areata (AA) is an autoimmune disorder characterized by immune-mediated attack on hair follicles, resulting in non-scarring hair loss. The collapse of hair follicle (HF) immune privilege (IP) is widely regarded as a central pathogenic mechanism in AA. While CD8⁺ T cells have been extensively studied in this context, the contribution of macrophages to disease initiation and progression remains less defined.
Methods: In this study, we investigated the roles of macrophages and CD8⁺ T cells in shaping immune cell recruitment and local immune dysregulation in AA lesions. Using single-cell transcriptomics, flow cytometry, and immunofluorescence during the development of an AA mouse model, we observed robust expansion and transcriptional reprogramming of CD8⁺ T cells, accompanied by prominent macrophage infiltration surrounding affected HFs.
Results: Interrogation of macrophage populations identified two transcriptionally distinct subpopulations: Folr2⁺ tissue-resident macrophages (TRMacs) and Folr2⁻ monocyte-derived macrophages (MoMacs). Each subset displayed unique gene-expression profiles enriched for pathways involved in T cell activation, leukocyte trafficking, and myeloid differentiation. Integration of spatial transcriptomic and flow cytometry imaging analyses revealed close spatial interactions between macrophage subsets and CD8⁺ T cells, with macrophage abundance positively correlating with CD8⁺ T cell infiltration. To assess functional relevance, we depleted macrophages with an antibody directed against colony-stimulating factor 1 receptor (CSF1R) in AA-grafted mice. Macrophage ablation markedly reduced both hair loss severity and the accumulation of cytotoxic NKG2D⁺ CD8⁺ T cells in lesional skin.
Conclusion: Together, these findings support that macrophages play a pivotal role in driving local immune dysregulation in AA. Targeting macrophage subsets may represent a promising therapeutic approach for restoring HF immune privilege and ameliorating disease progression.
