All-trans retinoic acid and rapamycin synergize with transforming growth factor-β1 to induce regulatory T cells but confer different migratory capacities

J Leukoc Biol. 2013 Nov;94(5):981-9. doi: 10.1189/jlb.0312167. Epub 2013 Jul 29.


Tregs play important roles in maintaining immune homeostasis, and thus, therapies based on Treg are promising candidates for the treatment for a variety of immune-mediated disorders. These therapies, however, face the significant challenge of obtaining adequate numbers of Tregs from peripheral blood that maintains suppressive function following extensive expansion. Inducing Tregs from non-Tregs offers a viable alternative. Different methods to induce Tregs have been proposed and involve mainly treating cells with TGF-β-iTreg. However, use of TGF-β alone is not sufficient to induce stable Tregs. ATRA or rapa has been shown to synergize with TGF-β to induce stable Tregs. Whereas TGF-β plus RA-iTregs have been well-described in the literature, the phenotype, function, and migratory characteristics of TGF-β plus rapa-iTreg have yet to be elucidated. Herein, we describe the phenotype and function of mouse rapa-iTreg and reveal that these cells differ in their in vivo homing capacity when compared with mouse RA-iTreg and mouse TGF-β-iTreg. This difference in migratory activity significantly affects the therapeutic capacity of each subset in a mouse model of colitis. We also describe the characteristics of iTreg generated in the presence of TGF-β, RA, and rapa.

Keywords: Treg migration; adoptive cell therapy; chemokines; inflammatory bowel disease; live-animal imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / analysis
  • Cell Movement / drug effects
  • Drug Synergism
  • Integrin alpha Chains / analysis
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CCR / analysis
  • Sirolimus / pharmacology*
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / physiology
  • Transforming Growth Factor beta1 / pharmacology*
  • Tretinoin / pharmacology*


  • Antigens, CD
  • CC chemokine receptor 9
  • Integrin alpha Chains
  • Receptors, CCR
  • Transforming Growth Factor beta1
  • alpha E integrins
  • Tretinoin
  • Sirolimus