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Generation of CD4⁺ or CD8⁺ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction

From the Laboratory of Experimental Oncology D, National Cancer Research Institute, 16132-Genoa, Italy (CP, PC, AP); Laboratory of Tumor Immunology, San Raffaele Scientific Institute, 20132, Milan, Italy (MZ, MRZ)

Correspondence: Alessandro Poggi, PhD, MD, National Cancer Research Institute (IST) Genoa, Laboratory of Experimental Oncology D, Department of Translational Oncogenesis, Largo R. Benzi 10, 16132 Genoa, Italy. E-mail: alessandro.poggi{at}istge.it

Background and Objectives: Mesenchymal stem cells (MSC) have been proposed as a way to treat graft-versus-host disease based on their immunosuppressive effect. We analyzed whether regulatory T cells can be generated in co-cultures of peripheral blood mononuclear cells (PBMC) and MSC.

Design and Methods: MSC were obtained from the bone marrow of four healthy donors and nine patients with acute leukemia in complete remission following chemotherapy. Short-term (4 days) co-cultures of MSC and autologous or allogeneic PBMC were set up, the lymphocytes harvested and their regulatory activity assessed.

Results: Lymphocytes harvested from MSC-PBMC co-cultures strongly inhibit (up to 95%) mixed lymphocyte reaction (MLR), recall to alloantigen, and CD3- or phytohemagglutinin-induced lymphocyte proliferation. These lymphocytes, termed regulatory cells (Reg_c), were all CD45⁺CD2⁺ with variable proportions of CD25⁺ cells (range 40–75% n=10) and a minor fraction expressed CTLA4 (2–4%, n=10) or glucocorticoid-induced tumor necrosis factcor receptor-related gene (0.5–4% n=10). Both CD4⁺ and CD8⁺ Reg_c purified from MSC-PBMC co-cultures strongly inhibited lymphocyte proliferation at a 1:100 Reg_c:responder cell ratio. CD4⁺ Reg_c expressed high levels of forkhead box P3 (Foxp3) mRNA while CD8⁺ Reg_c did not. The effectiveness of Reg_c, whether CD4⁺ or CD8⁺, was 100-fold higher than that of CD4⁺CD25^+high regulatory T cells. Reg_c were also generated from highly purified CD25^– PBMC or CD4⁺ or CD8⁺ T cell subsets. Soluble factors, such as interleukin-10, transforming growth factor-ß and prostaglandin E₂ did not appear to be involved in the generation of Reg_c or in the Reg_c-mediated immuno-suppressive effect. Furthermore, cyclosporine A did not affect Reg_c generation or the immunosuppression induced by Reg_c.

Interpretation and Conclusions: These findings indicate that powerful regulatory CD4⁺ or CD8⁺ lymphocytes are generated in co-cultures of PBMC with MSC. This strongly suggests that these regulatory cells may amplify the reported MSC-mediated immunosuppressive effect.

Key words: mesenchymal stem cells, regulatory CD4⁺ T cells, regulatory CD8⁺ T cells, lymphocyte triggering.

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