title: Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells.
abstract: Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.
authors.affiliation: Clinical Investigator Development Program and 2 Experimental Transplantation and Immunology Branch, 3 Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Sean P
authors.initials: SP
authors.lastname: Spencer
authors.forename: Parizad
authors.initials: P
authors.lastname: Torabi-Parizi
authors.forename: John R
authors.initials: JR
authors.lastname: Grainger
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Scott
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hall
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Ferreyra
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Leonardi
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Borman
authors.forename: Jinshan
authors.initials: J
authors.lastname: Wang
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Christoph
authors.initials: C
authors.lastname: Wilhelm
authors.forename: Rongman
authors.initials: R
authors.lastname: Cai
authors.forename: Junfeng
authors.initials: J
authors.lastname: Sun
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Napoli
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000528:radiation effects; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000528:radiation effects; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity / Q000276:immunology; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D014212:Tretinoin / Q000378:metabolism*; D014801:Vitamin A / Q000378:metabolism; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D000949:Histocompatibility Antigens Class II; D018168:Receptors, Retinoic Acid; D014801:Vitamin A; D014212:Tretinoin