title: Vitamins A and D have antagonistic effects on expression of effector cytokines and gut-homing integrin in human innate lymphoid cells.
abstract: BACKGROUND
  Retinoic acid (RA), the main biologically active metabolite of vitamin A, is known to promote gut homing of lymphocytes, as well as various regulatory and effector immune responses. In contrast, the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is predominantly immunosuppressive. Little is known about the direct effects of these vitamins on the recently identified innate lymphoid cells (ILCs).
  
  
  OBJECTIVE
  We sought to characterize the effects of RA and 1,25D3 on human ILCs.
  
  
  METHODS
  Peripheral blood mononuclear cells were isolated from 27 non-selected blood donor buffy coats, and ILCs were sorted by FACS. ILC1, ILC2, and ILC3 cells were cultured for 5 days with RA, 1,25D3, and various cytokines known to activate ILCs (IL-2, IL-7, IL-12, thymic stromal lymphopoietin (TSLP), IL-25, and IL-33). Cytokines produced by ILCs were measured in culture supernatants, and surface receptor expression was analysed by flow cytometry.
  
  
  RESULTS
  Retinoic acid acted synergistically with IL-2 and other activating cytokines to induce expression of the gut-homing integrin α4β7 in ILCs, as well as production of IL-5 and IL-13 in ILC2 cells, and IFN-γ in ILC1 and ILC3 cells. Expression of integrin α4β7 and cytokine production in ILCs stimulated with RA + IL-2 was increased at least fourfold as compared to ILCs cultured with RA or IL-2 alone. In contrast, RA completely inhibited the IL-2-induced expression of cutaneous lymphocyte antigen (CLA) in ILCs. Moreover, addition of 1,25D3 to ILCs cultured with RA + IL-2 inhibited cytokine production and expression of integrin α4β7 by at least 30%.
  
  
  CONCLUSIONS
  Retinoic acid and 1,25D3 have antagonistic effects on the expression of effector cytokines and gut-homing integrin by human ILCs. The balance between these vitamins may be an important factor in the functioning of ILCs and the diseases in which ILCs are implicated, such as allergic inflammation.
authors.affiliation: Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ruiter
authors.affiliation: Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Food Allergy Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: S U
authors.initials: SU
authors.lastname: Patil
authors.affiliation: Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Food Allergy Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Shreffler
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D014801:Vitamin A / Q000494:pharmacology*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D016023:Integrins; C118756:dihydroxy-vitamin D3; C071777:integrin alpha4beta7; D014801:Vitamin A; D014807:Vitamin D
keywords: Human; ILC2; cytokines; gut-homing integrin; innate lymphoid cells; vitamin A; vitamin D