T-Helper Cell Subsets in Experimental Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation. Most of the knowledge about the pathophysiology of acute GVHD has been derived from studies of mouse models.

T cells are central to the pathophysiology of GVHD. Activated T cells are generally classified as Th1 (secreting IL-2 and IFN-γ) or Th2 (secreting IL-4, IL-5, IL-10, and IL-13). Researchers have considered acute GVHD to be a Th1-type disease on the basis of the predominance of cytotoxic T cell-mediated pathology and of increased production of Th1-type cytokines, including IFN-γ, detectable in the serum or donor T cells during acute GVHD. However, several recent studies have suggested that the influence of Th1 and Th2 cytokines in acute and chronic GVHD is not so simply explained.¹  More recently, a third T-helper subset has been described, namely Th17 (secreting Il-17), that has been implicated in antifungal defense mechanisms and in the pathogenesis of autoimmune disease and (although controversial) in the genesis of experimental acute GVHD.

In this article, Defu Zeng’s group from City of Hope aimed to clarify the respective role of the different T cell subsets in acute experimental GVHD. Their study was based on the following background: Although acute GVHD has been proposed to be mediated by Th1 cells, donor T cells deficient in IFN-γ induced worse acute GVHD. Although Th2 cells were reported to suppress acute GVHD, Th2- biased STAT4 null donor cells induced lethal GVHD. Th17 cells were reported to be a potent inflammatory mediator in some autoimmune diseases, but these authors previously showed that absence of Th17 cells led to exacerbated acute GVHD. Th17 cells, however, were also shown to augment GVHD in some circumstances, and in vitro-generated Th17 cells were shown to mediate the lung and skin disease in acute GVHD.¹ 

In this study, the authors used an MHC-mismatched model of GVHD. If they used wild-type mice donor CD4+ T cells, these T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in the gut and liver. However, absence of IFN-γ in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in the lung and skin; absence of both IL-4 and IFN-γ resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in the skin; absence of both IFN-γ and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was, in part, associated with their tissue-specific migration mediated by differential expression of chemokine receptors.