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.
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.
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.
Collectively, these studies may define macrophage—Treg crosstalk as an important determinant of immune disequilibrium and tissue injury in oral cGVHD.
Intramural program of the NIDCR, NIH
Transplantation Immunology (TRAN)
Rubina Sharma, Ana Costa da Silva, Noemi Kedei et al.· Journal of Immunology· 0 citations
Ocular graft-versus-host disease severity correlates with inflammation and fibrotic damage in the lacrimal gland (LG). Long-living stem-like progenitor exhausted TCF1+ PD-1+ T cells (Tpex) have been reported to maintain and replenish the reservoir of exhausted-like effector T cells (Texef). In chronic settings, the cumulative cytotoxicity of CD8+ Texef mediates tissue damage. A comprehensive characterization of the phenotypic and transcriptomic profiles of these pathogenic exhausted populations has not yet been reported.
To this end, we used an established minor MHC-mismatched murine model of sclerodermatous cGVHD (B10.D2 (H-2d) into BALB/c (H-2d), allogeneic (allo) cGVHD) using syngeneic (syn) controls (Balb/c into Balb/c) assessed at 14-, 21-, and 42-days post-transplant. Here, we longitudinally investigated transcriptional changes in exocrine tissue immune population.
Microscopy identified increased lymphocyte infiltration in the lacrimal gland and conjunctiva. Single cell sequencing was performed on lacrimal gland. Datasets were processed using a robust integrative approach based on scVI deep learning architecture. We identified four distinct exhausted T cell subpopulations expanded in allo LG. Exhaustion, cytotoxic and residency scores were highest for these four subsets. Proportional distribution analysis revealed a substantial early increase in Tcf7+, Sell+, Il7r+, Slamf6+, Pdcd1+ CD8+ Tpex cells in the allo group. Importantly, allo lacrimal glands were marked by the expansion of Tcf7− CD8+ Texef cells that were not present in the syn group. Cell-cell communication analyses inferred an interaction between Tfrchi acinar cells and exhausted T cells through Ceacam1-Havcr2, signaling shown to drive terminal exhaustion of Texef.
Overall, scRNAseq results evince a major shift in T-cell fate towards a pathogenic exhausted-like phenotype possibly stemming from an early Tcf7+ expressing precursor exhausted population in cGVHD-affected LG.
Intramural program of the NIDCR, NIH
Transplantation Immunology (TRAN)
C. Basset, Marit Aure, Rubina Sharma et al.· Journal of Immunology· 0 citations
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