CD70 identifies alloreactive T cells and represents a potential target for prevention and treatment of acute GvHD.
Kriti VermaWayne CroftSandra Margielewska-DaviesHayden PearceChristine StephensDiana DiaconescuSarah BevingtonCharles CraddockRasoul Amel-KashipazJianmin J ZuoFrancesca A M KinsellaPaul A H MossPublished in: Blood advances (2024)
Graft-versus-host disease (GvHD) remains a major challenge following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and further understanding of its immunopathology is crucial for developing new treatments. CD70 interacts with CD27 and is upregulated transiently on T cells following recent TCR engagement. Here we investigated the functional and clinical significance of CD70 expression on T cells during the early post-transplantation period. CD70 was expressed on a subset of highly activated memory T cells within the first 2 weeks post-transplant which then gradually declined in most patients. CD70+ T cells exhibited an open chromatin landscape and a transcriptional profile indicative of intense MYC-driven glycolysis and proliferation. CD4+ and CD8+ CD70+ T cell number increased by 9-fold and 4-fold respectively during acute GvHD (aGvHD) and displayed an oligoclonal TCR repertoire. These cells expressed CCR4 and CCR6 chemokine receptors and were markedly increased in aGvHD tissue samples. Furthermore, CD70+ T cells demonstrated alloreactive specificity in vitro and proliferative and inflammatory cytokine responses were markedly attenuated by CD70 blockade. These findings identify CD70 as a marker of highly activated alloreactive T cells and reveal the potential therapeutic importance of inhibiting CD27-CD70 co-stimulation in both the prophylaxis and treatment of aGvHD.
Keyphrases
- allogeneic hematopoietic stem cell transplantation
- nk cells
- gene expression
- transcription factor
- regulatory t cells
- acute myeloid leukemia
- dendritic cells
- genome wide
- newly diagnosed
- signaling pathway
- ejection fraction
- risk assessment
- cell death
- dna methylation
- high resolution
- bone marrow
- working memory
- cell therapy
- cell cycle arrest
- acute respiratory distress syndrome
- replacement therapy
- endoplasmic reticulum stress
- structural basis
- mechanical ventilation