Postdoctoral fellow National Institutes of Health Bethesda, Maryland, United States
Disclosure(s):
Rubina Sharma, PhD: No financial relationships to disclose
Introduction/Rationale: Chronic graft-versus-host disease (cGVHD) is an alloimmune complication of allogeneic hematopoietic stem cell transplantation driven by donor–recipient antigen mismatch. The oral mucosa is a frequent target; however, the cellular circuitry and spatial architecture that sustain oral cGVHD remain incompletely defined.
Methods: Using single-cell RNA sequencing, we observed a marked enrichment of macrophage subsets in cGVHD oral mucosa. Spatial transcriptomics mapped CD68+ macrophages preferentially along the epithelial basement membrane. Ultrahigh-plex spatial phenotyping further delineated a significant expansion of proinflammatory (M1-like) macrophages, defined by HLA-DR, CD86 expression, accompanied by elevated IL-17 within lesional regions.
Results: These data suggest an IL-17–driven axis in M1 macrophage recruitment and activation that may amplify mucosal inflammation. Spatial proximity analyses demonstrated juxtaposition of M1 macrophages with CD4+ regulatory T cells (Tregs) in cGVHD tissue, yet TIGIT+ Tregs were comparatively reduced, consistent with impaired regulatory–myeloid crosstalk. Ligand–receptor inference identified upregulation of JAK-STAT signaling, including increased CXCL10–CXCR3 interactions, suggesting chemokine-guided positioning of effector cells. Clinically, strategies that expand Tregs or antagonize CSF1R to limit macrophage activity have shown benefit in cGVHD, underscoring the therapeutic relevance of these pathways. Co-culture assays with macrophage-Treg cells are needed to probe reciprocal effects on cytokine production, Treg suppressive capacity, and macrophage polarization with verification in cGVHD patients.
Conclusion: Collectively, these studies may define macrophage–Treg crosstalk as an important determinant of immune disequilibrium and tissue injury in oral cGVHD.
