Therapies based on regulatory T cells (Treg) hold great promise for promotion of transplant tolerance. Additionally, recent insights in Treg function have underscored the importance of the distribution pattern of Treg for maximal protective activity. Being that the frequency of naturally-occurring Treg in the blood is extremely low, inducing Treg (iTreg) from non-Treg has been suggested as a viable alternative. We have then compared the functional and migratory properties of iTreg induced in presence of all-trans retinoic acid (RA) or rapamycin (Rapa) – two molecules known to synergize with TGF-Β to induce stable iTreg.

Following in vitro activation of mouse CD4⁺CD25^– T cells, addition of RA or Rapa increased the frequency of Foxp3⁺ cells over the proportion obtained with TGF-Β alone. No significant differences were found in the expression of Treg-associated markers: CTLA-4, CD25, and GITR. All three iTreg types were comparable in their ability to inhibit T cell activation in vitro. Major differences were evident, however, in the expression of chemokine receptors and integrins: TGFΒ-iTreg were CCR9^loCD103^hi; RA-iTreg were CCR9^hiCD103^hi, and Rapa-iTreg were CCR7^hiCCR9^loCD103^lo. This suggested different migratory properties. Monitoring the intensity of bioluminescent signal from mice adoptively-transferred with luciferase-expressing iTreg confirmed that Rapa-iTreg had a greater tendency to accumulate in lymph nodes, while RA-iTreg accumulated outside of lymphoid tissues, mainly in the gut. These different migratory properties translated into different protective capacity. In a mouse model of inflammatory bowel disease (based on adoptive transfer of T cells with or without iTreg), Rapa-iTreg exerted the strongest protective effect, correlating with their ability to suppress the activation of colitogenic T cells in the mesenteric lymph node.

These results indicate that although RA and Rapa are considered interchangeable in their promotion of stable iTreg, they confer a different migratory potential that translates in different abilities to control local immune responses in vivo. Based on our results, we envision interventions that employ iTreg “optimized” for the specific type and stage of disease to be treated.

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