Epithelial expression of the cytosolic retinoid chaperone cellular retinol binding protein II is essential for in vivo imprinting of local gut dendritic cells by lumenal retinoids.
Dendritic cells (DCs) use all-trans retinoic acid (ATRA) to promote characteristic intestinal responses, including Foxp3(+) Treg conversion, lymphocyte gut homing molecule expression, and IgA production. How this ability to generate ATRA is conferred to DCs in vivo remains largely unstudied. Here, we observed that among DCs, retinaldehyde dehydrogenase (ALDH1), which catalyzes the conversion of retinal to ATRA, was preferentially expressed by small intestine CD103(+) lamina propria (LP) DCs. Retinoids induced LP CD103(+) DCs to generate ATRA via ALDH1 activity. Either biliary or dietary retinoids were required to confer ALDH activity to LP DCs in vivo. Cellular retinol-binding protein II (CRBPII), a cytosolic retinoid chaperone that directs enterocyte retinol and retinal metabolism but is redundant to maintain serum retinol, was required to confer ALDH activity to CD103(+) LP DCs. CRBPII expression was restricted to small intestine epithelial cells, and ALDH activity in CRBPII(-/-) DCs was restored by transfer to a wild-type recipient. CD103(+) LP DCs from CRBPII(-/-) mice had a decreased capacity to promote IgA production. Moreover, CD103(+) DCs preferentially associated with the small intestine epithelium and LP CD103(+) DC ALDH activity, and the ability to promote IgA production was reduced in mice with impaired DC-epithelia associations. These findings demonstrate in vivo roles for the expression of epithelial CRBPII and lumenal retinoids to imprint local gut DCs with an intestinal phenotype.
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Keely G
KG
McDonald
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Matthew R
MR
Leach
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Kaitlin W M
KWM
Brooke
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Caihong
C
Wang
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Leroy W
LW
Wheeler
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Elyse K
EK
Hanly
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Christopher W
CW
Rowley
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; Department of Medicine, St. Louis VA Medical Center, St. Louis, Missouri.
Marc S
MS
Levin
Department of Cell Biology, The State University of New York, Downstate Medical Center, Brooklyn, New York.
Michael
M
Wagner
Department of Internal Medicine, The State University of New York, Stony Brook, New York.
Ellen
E
Li
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Electronic address: rnewberry@wustl.edu.
Rodney D
RD
Newberry
D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D007111:Immunity, Cellular / Q000502:physiology; D007070:Immunoglobulin A / Q000096:biosynthesis*; D039001:Integrin alpha Chains / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010641:Phenotype; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D054840:Retinol-Binding Proteins, Cellular / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
D015703:Antigens, CD; D007070:Immunoglobulin A; D039001:Integrin alpha Chains; D015850:Interleukin-6; D007527:Isoenzymes; C518460:Rbp2 protein, mouse; D054840:Retinol-Binding Proteins, Cellular; C091367:alpha E integrins; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase