Abstract
The C-type lectin-like receptor CD161 is a well-established marker for human IL17-producing T cells, which have been implicated to contribute to the development of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). In this study, we analyzed CD161+ T cell recovery, their functional properties and association with GVHD occurrence in allo-SCT recipients. While CD161+CD4+ T cells steadily recovered, CD161hiCD8+ T cell numbers declined during tapering of Cyclosporine A (CsA), which can be explained by their initial growth advantage over CD161neg/lowCD8+ T cells due to ABCB1-mediated CsA efflux. Interestingly, occurrence of acute and chronic GVHD was significantly correlated with decreased levels of circulating CD161+CD4+ as well as CD161hiCD8+ T cells. In addition, these subsets from transplanted patients secreted high levels of IFNγ and IL17. Moreover, we found that CCR6 co-expression by CD161+ T cells mediated specific migration towards CCL20, which was expressed in GVHD biopsies. Finally, we demonstrated that CCR6+ T cells indeed were present in these CCL20+ GVHD-affected tissues. In conclusion, we showed that functional CD161+CCR6+ co-expressing T cells disappear from the circulation and home to GVHD-affected tissue sites. These findings support the hypothesis that CCR6+CD161-expressing T cells may be involved in the immune pathology of GVHD following their CCL20-dependent recruitment into affected tissues.
Highlights
Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality after allogeneic stem cell transplantation [1]
CD161-expressing T cells display high levels of the chemokine receptor CCR6, for which we recently showed that a single nucleotide polymorphism in this gene correlates with occurrence of chronic GVHD [33]
Th17 cells have been linked to the pathophysiology of GVHD, data remains limited and contradictory [8,9,10,11,12,13,14,15]
Summary
Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality after allogeneic stem cell transplantation (allo-SCT) [1]. The pathophysiology of GVHD is a multistep process involving tissue damage and pro-inflammatory cytokine cascades induced by the pre-transplant conditioning regimen [1,2]. This results in an excessive inflammatory environment in which donor-derived CD4+ and CD8+ T cells become potently activated. Macrophages, and other effector T cells subsets are recruited, resulting in further enhancement of GVHD [1,3,4,5]. Th1-type CD4+ T cells and Tc1-type CD8+ T cells play an important role in GVHD pathophysiology [6,7], but other T cell subsets with specific phenotype and functional characteristics might play a pivotal role as well
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