Figure 4.
Upregulation of transcriptional activation markers in effector T cell subsets before aGVHD onset after posttransplant cyclophosphamide. Tconv but not CD8+ T cell changes support selective role for CD4+ T cells in aGVHD after PTCy. Analysis of DEGs in Tconv identifies proinflammatory skewing that proceeds aGVHD occurrence. (A) Hierarchical clustering of significantly regulated genes identified in Tconv RNA-Seq (aGVHD n = 6; GVHD-free n = 6) shows a greater differential regulation of gene expression with an enhancement of type 1 interferon response and Th1 skewing is the cohort of patients with aGVHD. (B) CXCR3, a key receptor for CXCL9, is upregulated on circulating allogeneic Tconv prior to the development of clinical post-PTCy breakthrough GVHD. Matched donor alloBMT patient samples were analyzed by flow cytometry for expression of CXCR3 on Tconv, including the Th17-prone CD146+CCR5+ subset. Representative flow cytometry panels are shown. (C) Gene set enrichment analyses validate Tconv and CD8+ T cell activation during aGVHD, but not enhanced activity of Notch and IL-6/JAK/STAT pathways that have been associated in other studies with pathogenic alloresponse. Tconv (red) and CD8+T cells (blue) analyses were performed using GSEA and Hallmark and c7 (immunologic signature) datasets from the MSigDb. (D) Transcriptional exhaustion is not associated with GVHD protection. Custom GSEA was performed using deposited datasets defining transcriptional hallmarks of functional T cell subsets. aGVHD development was associated with Tconv activation and loss of naïve signature. (E,F) Development of operational tolerance after PTCy is not associated with the acquisition of transcriptional exhaustion signature in CD8+T cells or Tconv, but enhanced emergence of naïve effector T cell phenotypes. Comparative GSEA of day 180 CD8+T cells (E) and Tconv (F) gene expression signatures from GVHD-free patients shows persistent lack of enrichment for exhaustion with progressive evolution of naïve phenotype, suggestive of evolving immune reconstitution.

Upregulation of transcriptional activation markers in effector T cell subsets before aGVHD onset after posttransplant cyclophosphamide. Tconv but not CD8+ T cell changes support selective role for CD4+ T cells in aGVHD after PTCy. Analysis of DEGs in Tconv identifies proinflammatory skewing that proceeds aGVHD occurrence. (A) Hierarchical clustering of significantly regulated genes identified in Tconv RNA-Seq (aGVHD n = 6; GVHD-free n = 6) shows a greater differential regulation of gene expression with an enhancement of type 1 interferon response and Th1 skewing is the cohort of patients with aGVHD. (B) CXCR3, a key receptor for CXCL9, is upregulated on circulating allogeneic Tconv prior to the development of clinical post-PTCy breakthrough GVHD. Matched donor alloBMT patient samples were analyzed by flow cytometry for expression of CXCR3 on Tconv, including the Th17-prone CD146+CCR5+ subset. Representative flow cytometry panels are shown. (C) Gene set enrichment analyses validate Tconv and CD8+ T cell activation during aGVHD, but not enhanced activity of Notch and IL-6/JAK/STAT pathways that have been associated in other studies with pathogenic alloresponse. Tconv (red) and CD8+T cells (blue) analyses were performed using GSEA and Hallmark and c7 (immunologic signature) datasets from the MSigDb. (D) Transcriptional exhaustion is not associated with GVHD protection. Custom GSEA was performed using deposited datasets defining transcriptional hallmarks of functional T cell subsets. aGVHD development was associated with Tconv activation and loss of naïve signature. (E,F) Development of operational tolerance after PTCy is not associated with the acquisition of transcriptional exhaustion signature in CD8+T cells or Tconv, but enhanced emergence of naïve effector T cell phenotypes. Comparative GSEA of day 180 CD8+T cells (E) and Tconv (F) gene expression signatures from GVHD-free patients shows persistent lack of enrichment for exhaustion with progressive evolution of naïve phenotype, suggestive of evolving immune reconstitution.

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