Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality

Govindarajan Thangavelu, Yu Chi Lee, Michael Loschi, K. Melanie Schaechter, Colby J. Feser, Brent H. Koehn, Elizabeth C. Nowak, Robert Zeiser, Jonathan S. Serody, William J. Murphy, David H Munn, Pierre Chambon, Randolph J. Noelle, Bruce R. Blazar

Research output: Contribution to journalArticle

Abstract

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 a 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.

Original languageEnglish (US)
Pages (from-to)2795-2805
Number of pages11
JournalJournal of Immunology
Volume202
Issue number9
DOIs
StatePublished - May 1 2019

Fingerprint

Retinal Dehydrogenase
Aldehyde Dehydrogenase
Graft vs Host Disease
Tretinoin
Dendritic Cells
Retinaldehyde
Protein Isoforms
T-Lymphocytes
Epithelial Cells
Retinoic Acid Receptors
Cell Lineage
Regulatory T-Lymphocytes
Enzymes
Intestines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Thangavelu, G., Lee, Y. C., Loschi, M., Melanie Schaechter, K., Feser, C. J., Koehn, B. H., ... Blazar, B. R. (2019). Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality. Journal of Immunology, 202(9), 2795-2805. https://doi.org/10.4049/jimmunol.1800899

Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality. / Thangavelu, Govindarajan; Lee, Yu Chi; Loschi, Michael; Melanie Schaechter, K.; Feser, Colby J.; Koehn, Brent H.; Nowak, Elizabeth C.; Zeiser, Robert; Serody, Jonathan S.; Murphy, William J.; Munn, David H; Chambon, Pierre; Noelle, Randolph J.; Blazar, Bruce R.

In: Journal of Immunology, Vol. 202, No. 9, 01.05.2019, p. 2795-2805.

Research output: Contribution to journalArticle

Thangavelu, G, Lee, YC, Loschi, M, Melanie Schaechter, K, Feser, CJ, Koehn, BH, Nowak, EC, Zeiser, R, Serody, JS, Murphy, WJ, Munn, DH, Chambon, P, Noelle, RJ & Blazar, BR 2019, 'Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality', Journal of Immunology, vol. 202, no. 9, pp. 2795-2805. https://doi.org/10.4049/jimmunol.1800899
Thangavelu G, Lee YC, Loschi M, Melanie Schaechter K, Feser CJ, Koehn BH et al. Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality. Journal of Immunology. 2019 May 1;202(9):2795-2805. https://doi.org/10.4049/jimmunol.1800899
Thangavelu, Govindarajan ; Lee, Yu Chi ; Loschi, Michael ; Melanie Schaechter, K. ; Feser, Colby J. ; Koehn, Brent H. ; Nowak, Elizabeth C. ; Zeiser, Robert ; Serody, Jonathan S. ; Murphy, William J. ; Munn, David H ; Chambon, Pierre ; Noelle, Randolph J. ; Blazar, Bruce R. / Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality. In: Journal of Immunology. 2019 ; Vol. 202, No. 9. pp. 2795-2805.
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