title: All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells.
abstract: OBJECTIVE
  All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear.
  
  
  METHODS
  We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease.
  
  
  RESULTS
  Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-gamma-producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17--or IL-4-producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell-dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion.
  
  
  CONCLUSIONS
  These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells.
authors.affiliation: Division of Immunology, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors.forename: Yang-Hau
authors.initials: YH
authors.lastname: Van
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Lee
authors.forename: Serina
authors.initials: S
authors.lastname: Ortiz
authors.forename: Mi-Heon
authors.initials: MH
authors.lastname: Lee
authors.forename: Han-Jun
authors.initials: HJ
authors.lastname: Qin
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D053804:Granzymes / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D015847:Interleukin-4; D014212:Tretinoin; D007371:Interferon-gamma; D053804:Granzymes