Cellular and molecular profiling of T-cell subsets at the onset of human acute GVHD

Abstract

The cellular and molecular processes involved in acute graft-versus-host disease (aGVHD) development early after allogeneic hematopoietic cell transplantation (HCT) in humans remain largely unknown. We have performed multiparameter immunophenotyping and molecular profiling of CD4+ and CD8+ T cells in 2 independent cohorts of patients undergoing HCT, as well as in their HLA-identical sibling donors. Cellular profiling using spectral flow cytometry showed an incomplete reconstitution of the T-cell compartment in recipients without aGVHD early after transplantation, as well as a shift toward an effector memory phenotype, paralleled by depletion of the naive T-cell pool. Molecular profiling of T-cell populations in donors vs recipients without aGVHD revealed increased pathway activity of >40 gene modules in recipients. These pathways were associated in particular with T-cell activation, adhesion, migration, and effector functions. Cellular profiles from recipients developing aGVHD displayed an enrichment of cells with a T memory stem cell–like phenotype compared with recipients without aGVHD. Comparison of gene profiles from these recipients revealed that transforming growth factor-β (TGF-β) signaling was most significantly downregulated, whereas the pathway activity of NF-κB–associated transcription factors and signaling pathways were increased, at aGVHD onset. This study suggests that the integration of cellular and molecular profiles provides new insights into the development of aGVHD in humans.

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

“…Additionally, the thymus of NSG mice atrophies shortly after birth and is completely absent by 4-6 weeks of age, negating the likelihood of de novo T cell production in these model systems. The same effector memory phenotype has also been identified in several primary human T cells clones taken from GVHD patients (49)(50)(51)(52). While there has not been a study directly investigating the capacity of isolated human memory T cells to mediate GVHD in a xenogeneic transplant model, studies using human umbilical cord blood T cells (which are all naïve CD45RA + T cells) also detect a universal transition to an effector memory phenotype several weeks after transplantation (47).…”

Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo

“… 17 Multianalyte profiling of culture supernatants was performed with Luminex xMAP technology (Myriad-RBM, Austin, Texas, USA), gene expression analysis with nCounter Technology (NanoString), with the Human Immunology v2 Gene Expression CodeSet. 18 19 …”

Human CD8 T‐stem cell memory subsets phenotypic and functional characterization are defined by expression of CD122 or CXCR3

“…In the data presented here, the T SCM CD122 hi subset had significantly upregulated Il12rb2 and Il18rap, along with the LN homing receptor and chemokine Ccr6 and Cxcr6, suggesting an activated memory-cell like transcriptomic profile that allows better ability to sense and respond to recall antigen challenge. By contrast, the T SCM CXCR3 hi subset had high expression of cytotoxicity-associated genes, such as Znf683 (also known as Hobit) and Il12rb1, and downregulated the memory-associated genes Klrf1 and Klrb1, as well as genes involved in T-cell stimulation and activation (Tryobp, Vav3, Gch1, and Efhd2), suggesting effector-cell like properties [64][65][66]. This finding is consistent with a recent report [52], which suggested that CXCR3-expressing T N cells are poised for effector potential.…”