Expansion of CD4+CD25+ regulatory T cells from cord blood CD4+ cells using the common γ-chain cytokines (IL-2 and IL-15) and rapamycin

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Rapamycin has important roles in the modulation of regulatory T cells. We tried to expand CD4+ CD25+ regulatory T cells (Treg cells) from umbilical cord blood (CB) CD4-positive cells using IL-15 or IL-2 with TGF-β and rapamycin. We were able to obtain more than 500-fold expansion of CD4+CD25+ cells from CB CD4+ cells using IL-15 and TGF-β with rapamycin. These expanded CD4+CD25+ cells expressed FoxP3 mRNA at a level about 100-fold higher and could suppress allogeneic mixed lymphocyte culture by more than 50%. Early after rapamycin stimulation, CB CD4+ cells showed increased expression of Foxp3 and a serine/threonine kinase Pim2 and sustained expression of negative PI3K regulator PTEN. On the other hand, CD4+CD25+ cells expanded with rapamycin for 8 days showed much higher levels of FoxP3 mRNA expression and decreased expression of PTEN. A comparison of IL-15 stimulation and IL-2 stimulation showed slightly higher efficiency of IL-15 for expansion of CD4+CD25+ cells and for FoxP3 expression, IL-15 also showed significantly higher efficacy for inhibition of MLC. The combination of the common γ-chain cytokine IL-15, TGF-β and rapamycin may be a useful means for expanding Treg cells. Pim2 expression early after stimulation with rapamycin may be important for conferring rapamycin resistance for growth of Treg cells. IL-15 is not less useful than IL-2 for expansion of Treg cells.
Springer Berlin / Heidelbergの論文