Aryl Hydrocarbon Receptor Deficient Donor T Cells Display Decreased Migration and Cause Reduced Or Enhanced Graft-Versus-Host Diseases In Different Transplant Models

• Published in: Blood 2013-11, Vol.122 (21), p.4477-4477
• Main Authors: Lin, Kaifeng Lisa, Fulton, LeShara M, Serody, Jonathan
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.4477.4477

The transcription factor aryl hydrocarbon receptor (AhR) is a cytosolic sensor of numerous small synthetic compounds (xenobiotics) and natural chemicals. Ligand binding of AhR causes a conformational change of the receptor, allowing its translocation to nucleus to regulate an array of genes. Different ligands could induce different sets of genes. AhR was first discovered as the mediator of dioxin toxicity. Its role in immunity was recently extensively investigated and expanded exponentially. Here we investigated the role of AhR in donor T cell-induced graft-versus-host diseases (GvHD) after bone marrow transplant in two MHC-mismatched models. B6D2 or Balb/c recipients were irradiated with one dose (950 rads for B6D2 and 800 rads for Balb/c) one day before transplant. C57BL/6 WT or AhR deficient (AhR KO) T cells were transplanted with T cell-depleted bone marrow to B6D2 or Balb/c, at a dose of three million T cells or five hundred thousand T cells, respectively. At different time points, recipient lymphoid organs or target organs were harvested and used for flow analysis or ELISA. A group of recipient mice were observed for an extended time to establish GvHD scores and survival curves. In B6 to B6D2 model, recipient mice transplanted with AhR KO T cells displayed lower GvHD scores and survived longer than mice transplanted with WT T cells (Figure 1C). We found that AhR KO donor T cells failed to accumulate in lymph nodes and spleen as rapidly as WT T cells as evident on day 1 and day 3 post-transplant (Figure 1A). Further investigation showed that the proliferation and cell death were similar between WT and AhR donor T cells, suggesting decreased migration of AhR KO T cells to lymphoid organs. It has been shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced AhR activation leads to the up-regulation of CCR4 and CCR5 in T cells, supporting our data that AhR affects cell migration. We also observed that lower percentage of AhR KO T cells produced IFN-g and IL-17 in lymph nodes and spleen early after transplant, but the differences disappeared at later time points (day 7). Colonic homogenates of AhR KO transplants contained less IFN-g, TNF-a, and IL-1a than WT transplants, which indicated that AhR KO T cells caused less inflammation in the gut (Figure 1B). Gut-associated injury due to inflammation is the major cause of death in this model. [Display omitted] However, in B6 to Balb/c model, recipient mice transplanted with AhR KO T cells displayed the op