1. Institute of Biomedical Chemistry, Moscow, Russia 2. Research Center of Neurology, Moscow, Russia 3. Department of Biochemistry, Peoples Friendship University of Russia (RUDN University), Moscow, Russia 4. Institute of Biomedical Chemistry, Moscow, Russia; Department of Biochemistry, Peoples Friendship University of Russia (RUDN University), Moscow, Russia
Regulatory T-cells CD4⁺CD25⁺FoxP3⁺CD127low (Tregs) play a key role in the maintenance of tolerance to auto antigens, inhibit function of effector T and B lymphocytes, and provide a balance between effector and regulatory arms of immunity. Patients with autoimmune diseases have decreased Treg numbers and impaired suppressive activity. Transformed ex vivo autologous Tregs could restore destroyed balance of the immune system. We developed a method for Treg precursor cell cultivation. Following the method, we were able to grown up 300-400 million of Tregs cells from 50 ml of peripheral blood during a week. Transformed ex vivo Tregs are 90-95% CD4⁺CD25⁺FoxP3⁺CD127low and have increased expression of transcription genes FoxP3 and Helios. Transformed ex vivo Tregs have increased demethylation of FoxP3 promoter and activated genes of proliferation markers Cycline B1, Ki67 and LGALS 1. Transformed ex vivo Tregs have increased suppressive activity and up to 80-90% these cells secrete cytokines TNFα и IFNγ. Our data suggest transformed ex vivo autologous Tregs have genetic, immunophenotypic and functional characteristics for regulatory T-cells and further can be used for adoptive immunotherapy autoimmune diseases and inhibition of transplantation immunity.
Blinova V.G., Gladilina Y.A., Eliseeva D.D., Lobaeva T.A., Zhdanov D.D. (2022) Increased suppressor activity of transformed ex vivo regulatory T-cells in comparison with unstimulated cells of the same donor. Biomeditsinskaya Khimiya, 68(1), 55-67.
Blinova V.G. et al. Increased suppressor activity of transformed ex vivo regulatory T-cells in comparison with unstimulated cells of the same donor // Biomeditsinskaya Khimiya. - 2022. - V. 68. -N 1. - P. 55-67.
Blinova V.G. et al., "Increased suppressor activity of transformed ex vivo regulatory T-cells in comparison with unstimulated cells of the same donor." Biomeditsinskaya Khimiya 68.1 (2022): 55-67.
Blinova, V. G., Gladilina, Y. A., Eliseeva, D. D., Lobaeva, T. A., Zhdanov, D. D. (2022). Increased suppressor activity of transformed ex vivo regulatory T-cells in comparison with unstimulated cells of the same donor. Biomeditsinskaya Khimiya, 68(1), 55-67.
Hartigan-O'Connor D.J., Poon C., Sinclair E., McCune J.M. (2007) Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J. Immunol. Methods, 319, 41-52. CrossRef Scholar google search
Gambineri E., Torgerson T.R., Ochs H.D. (2003) Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr. Opin. Rheumatol., 15, 430-435. CrossRef Scholar google search
Rossetti M., Spreafico R., Saidin S., Chua C., Moshref M., Leong J.Y., Tan Y.K., Thumboo J., van Loosdregt J., Albani S. (2015) Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region. J. Immunol., 194, 113-124. CrossRef Scholar google search
Fontenot J.D., Gavin M.A., Rudensky A.Y. (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol., 4, 330-336. CrossRef Scholar google search
Thornton A.M., Korty P.E., Tran D.Q., Wohlfert E.A., Murray P.E., Belkaid Y., Shevach E.M. (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol., 184, 3433-3441. CrossRef Scholar google search
Callahan M.K., Postow M.A., Wolchok J.D. (2014) CTLA-4 and PD-1 pathway blockade: combinations in the clinic. Front. Oncol., 4, 385. CrossRef Scholar google search
Bono M.R., Fernández D., Flores-Santibáñez F., Rosemblatt M., Sauma D. (2015) CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression. FEBS Lett., 589(22), 3454-3460. CrossRef Scholar google search
Chen X., Oppenheim J.J. (2010) Oppenheim, TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Curr. Dir. Autoimmun., 11, 119-134. CrossRef Scholar google search
Booth N.J., McQuaid A.J., Sobande T., Kissane S., Agius E., Jackson S.E., Salmon M., Falciani F., Yong K., Rustin M.H., Akbar A.N., Vukmanovic-Stejic M. (2010) Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J. Immunol., 184, 4317-4326.