Recent studies have underscored the critical role of retinoic acid (RA) in the development of lineage-committed CD4 and CD8 T cells in vivo. We have shown that under acute graft-versus-host disease (GVHD) inflammatory conditions, RA is upregulated in the intestine and is proinflammatory, as GVHD lethality was attenuated when donor allogeneic T cells selectively expressed a dominant negative RA receptor α that blunted RA signaling. RA can function in an autocrine and paracrine fashion, and as such, the host cell lineage responsible for the production of RA metabolism and the specific RA-metabolizing enzymes that potentiate GVHD severity are unknown. In this study, we demonstrate that enhancing RA degradation in the host and to a lesser extent donor hematopoietic cells by overexpressing the RA-catabolizing enzyme CYP26A1 reduced GVHD. RA production is facilitated by retinaldehyde isoform-2 (RALDH2) preferentially expressed in dendritic cells (DCs). Conditionally deleted RA-synthesizing enzyme RALDH2 in host or to a lesser extent donor DCs reduced GVHD lethality. Improved survival in recipients with RALDH2-deleted DCs was associated with increased T cell death, impaired T effector function, increased regulatory T cell frequency, and augmented coinhibitory molecule expression on donor CD4 + T cells. In contrast, retinaldehydrogenase isoform-1 (RALDH1) is dominantly expressed in intestinal epithelial cells. Unexpectedly, conditional host intestinal epithelial cells RALDH1 deletion failed to reduce GVHD. These data demonstrate the critical role of both donor and especially host RALDH2 + DCs in driving murine GVHD and suggest RALDH2 inhibition or CYP26A1 induction as novel therapeutic strategies to prevent GVHD.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung, and Blood Institute, and by National Cancer Institute Grants R01 HL56067, HL1181879, and AI34495 (to B.R.B.). G.T. was supported by a Canadian Institutes of Health Research fellowship. We thank Dr. Angela Panoskaltsis-Mortari, Dr. Patricia Taylor, Dr. Mark Osborn, Andrew Kemal Kirchmeier, and Jamie Panthera for technical assistance and excellent animal husbandry.
Blood Institute, and by National Cancer Institute Grants R01 HL56067, HL1181879, and AI34495 (to B.R.B.). G.T. was supported by a Canadian Institutes of Health Research fellowship. Address correspondence and reprint requests to Dr. Bruce R. Blazar, Mayo Mail Code 109, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: firstname.lastname@example.org
This work was supported by grants from the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung, and
Copyright Ó 2019 by The American Association of Immunologists, Inc.
- Aldehyde Oxidoreductases/genetics
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/immunology
- Dendritic Cells/immunology
- Gene Expression Regulation, Enzymologic/immunology
- Graft vs Host Disease/genetics
- Mice, Inbred BALB C
- Mice, Transgenic
- Retinoic Acid 4-Hydroxylase/genetics
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural