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Review
. 2011 Mar 24;117(12):3268-76.
doi: 10.1182/blood-2010-12-290403. Epub 2011 Jan 18.

Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new

James M Coghill  1 , Stefanie Sarantopoulos, Timothy P Moran, William J Murphy, Bruce R Blazar, Jonathan S Serody
Affiliations
Review

Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new

James M Coghill et al. Blood. .

Abstract

GVHD is a syndrome that results from minor and major histocompatibility complex incompatibilities between the donor and recipient. More than 50 years after its initial description, the pathophysiology of GVHD remains poorly understood. Nonetheless, donor T cells have been shown to be critical to the pathophysiology of acute and chronic GVHD, yet precisely how they function remains unclear. The effector mechanisms by which donor T cells mediate tissue inflammation is even less well understood. Identification of several new lineages of CD4(+) T cells made in the past decade and their roles in the pathophysiology of T cell-mediated diseases has shed new light on these effector mechanisms. In this review, we summarize the recent descriptions of these T-cell lineages and the current data supporting their role in acute and to a lesser extent chronic GVHD. Investigations into the activity of these new T-cell lineages may provide more rationale approaches to the treatment or prevention of GVHD VSports手机版. .

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Figures

Figure 1
Figure 1
CD4+ T-cell effector subsets. Antigen-specific stimulation of naive CD4+ T cells in the presence of certain cytokines induces expression of lineage-specific transcription factors, resulting in differentiation into CD4+ T-cell effector subsets. IFN-γ and IL-12 lead to the expression of T-bet, resulting in Th1 cell differentiation. CD4+ T-cell activation in the presence of IL-4 results in Th2 cell development mediated by GATA3; however, the addition of TGF-β causes differentiation into Th9 cells. The combination of IL-6 and TGF-β is necessary for RORγt expression, resulting in Th17 cell development, whereas the presence of IL-6 alone or with other unknown cytokines possibly results in Th22 cell differentiation by expression of AHR. Finally, IL-21 appears to be important for the development of Tfh cells through induction of Bcl-6.
Figure 2
Figure 2
Th1 and Th2 cells in GVHD. Th1 cells play a significant role in GVHD pathogenesis in the gastrointestinal (GI) tract. Donor-specific Th1 cells migrate to the GI tract and liver by the chemokine receptors CCR9 and CCR5. During conditioning before transplantation, the integrity of the epithelial barrier is compromised, resulting in translocation of bacterial products and activation of local antigen presenting cells (APCs). These activated APCs secrete IL-12, which is necessary for Th1 cell development and expansion. Th1 cells secrete IFN-γ, which has dual roles in the GI tract. IFN-γ and TNF facilitate further Th1 cell development and activation of allospecific CTLs, resulting in tissue damage. Conversely, Th1-derived IFN-γ can induce the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in APCs, causing T-cell anergy and apoptosis. Th2 cells migrate to the lung by CCR4, where they secrete IL-4, IL-5, and IL-13. IL-4 and IL-13 act on lung epithelium, causing inflammation and tissue remodeling that ultimately leads to pulmonary fibrosis. IL-5 facilitates expansion of eosinophils (Eos) that are recruited to the lung by CCL11, which can further exacerbate lung tissue damage.
Figure 3
Figure 3
Th17 cells in GVHD. Th17 cells traffic to the lung and skin by CCR6, where they mediate tissue damage. In the lung, Th17 cells secrete IL-17A, IL-17F, and TNF, which induce secretion of proinflammatory cytokines and chemokines by epithelial cells. Th17-derived cytokines act directly on neutrophils (neut), resulting in production of matrix metalloproteinases (MMPs), reactive oxygen species (ROS), and TNF. In the skin, IL-17A and IL-17F produced by infiltrating Th17 cells cause the production of several proinflammatory cytokines and chemokines by keratinocytes, resulting in further leukocyte recruitment and local tissue damage. IL-22 is secreted byTh17 cells and possibly Th22 cells activated by Langerhan cells (LCs). IL-22 induces keratinocyte proliferation, resulting in acanthosis and cutaneous GVHD pathology.
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