Abstract
Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we developed a xenogeneic model of aGVHD in immunodeficient mice. Phenotypic characterization of xenoreactive T lymphocytes (TL) in diseased mice disclosed a massive infiltration of GVHD target organs by an original CD4+CD8+ TL subset. Immunophenotypic and transcriptional profiling shows that CD4+CD8+ TL comprise a major PD1+CD62L−/+ transitional memory subset (>60%) characterized by low level expression of cytotoxicity-related transcripts. CD4+CD8+ TL produce high IL-10 and IL-13 levels, and low IL-2 and IFN-γ, suggestive of regulatory function. In vivo tracking of genetically labeled CD4+ or CD8+ TL subsequently found that CD4+CD8+ TL mainly originate from chronically activated cytotoxic TL (CTL). On the other hand, phenotypic profiling of CD3+ TL from blood, duodenum or rectal mucosa in a cohort of allo-HSCT patients failed to disclose abnormal expansion of CD4+CD8+ TL independent of aGVHD development. Collectively, our results show that acquisition of surface CD4 by xenoreactive CD8+ CTL is associated with functional diversion toward a regulatory phenotype, but rule out a central role of this subset in the pathogenesis of aGVHD in allo-HSCT patients.
Highlights
Allogeneic hematopoietic stem-cell transplantation (HSCT) is an effective therapy for hematological malignancies
A major limitation of clinical studies based on analysis of circulating T lymphocytes (TL) in human HSCT recipients developing acute graft-versus-host disease (aGVHD) is to what extent they reflect the phenotypic and functional diversity of alloreactive T cells within aGVHD target organs
Comparison between irradiated (n = 24) and non-irradiated (n = 11) mice infused with huPBMC subsequently showed that, despite overall similar TL engraftment and expansion, the latters developed a milder form of the disease characterized by decreased weight loss and slightly delayed aGVHD onset
Summary
Allogeneic hematopoietic stem-cell transplantation (HSCT) is an effective therapy for hematological malignancies. While hematopoietic stem cells (HSC) ensure hematopoietic recovery, donor T lymphocytes (TL) display a dual activity. Capable of destroying residual tumor cells through the GraftVersus Leukemia reaction (GVL) they frequently cause acute Graft-Versus-Host Disease (aGVHD). Besides genetic disparity between donor and recipient, there is evidence that pro-inflammatory signals emanating from host tissues or organs injured by pre-transplants conditioning contribute to disease propagation [4]. Activation of donor and recipient antigen-presenting cells, as well as increased expression of adhesion and costimulatory molecules and high chemokine production levels [5], exacerbate donor T cells activation resulting in accelerated blood extravasation followed by in situ amplification within aGVHD target organs [6, 7]. Alloreactive TL mediate tissue destruction either directly through granzyme/perforin-dependent cytolytic activity or Fas/ FasL interactions [8, 9], or indirectly through the recruitment or activation of monocyte/macrophages and neutrophils
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