Relative Resistance of Human CD4+ Memory T Cells to Suppression by CD4+CD25+ Regulatory T Cells

• Published in: American journal of transplantation Vol. 11; no. 8; pp. 1734 - 1742
• Main Authors: Afzali, B., Mitchell, P. J., Scottà, C., Canavan, J., Edozie, F. C., Fazekasova, H., Lord, G. M., John, S., Barber, L. D., Hernandez‐Fuentes, M. P., Lechler, R. I., Lombardi, G.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.08.2011; Wiley
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Applied cell therapy and gene therapy; Autografts; Biological and medical sciences; CD154 antigen; CD25 antigen; CD4 antigen; CD4 Antigens - immunology; Cell proliferation; Cell Separation; Cell therapy; Cells, Cultured; Clinical trials; Cytokines; Flow Cytometry; Graft rejection; human; Humans; Immunologic Memory; Immunological memory; Immunological tolerance; Immunoregulation; Interleukin-2 Receptor alpha Subunit - immunology; Lymph nodes; Lymphocytes T; Medical sciences; Memory; Memory cells; memory T cells; naïve T cells; Peripheral blood; regulatory T cells; suppression; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes, Regulatory - immunology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Human; CD4 T lymphocyte; Immune response; Cell therapy; Suppression; Naive cell; memory T cells; Memory lymphocyte; Resistance; regulatory T cells; Treatment; T-Lymphocyte; naive T cells; Regulatory cell
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2011.03635.x

Successful expansion of functional CD4+CD25+ regulatory T cells (Treg) ex vivo under good manufacturing practice conditions has made Treg‐cell therapy in clinical transplant tolerance induction a feasible possibility. In animals, Treg cells home to both transplanted tissues and local lymph nodes and are optimally suppressive if active at both sites. Therefore, they have the opportunity to suppress both naïve and memory CD4+CD25− T cells (Tresp). Clinical transplantation commonly involves depleting therapy at induction (e.g. anti‐CD25), which favors homeostatic expansion of memory T cells. Animal models suggest that Treg cells are less suppressive on memory, compared with naïve Tresp that mediate allograft rejection. As a result, in the context of human Treg‐cell therapy, it is important to define the effectiveness of Treg cells in regulating naïve and memory Tresp. Therefore, we compared suppression of peripheral blood naïve and memory Tresp by fresh and ex vivo expanded Treg cells using proliferation, cytokine production and activation marker expression (CD154) as readouts. With all readouts, naïve human Tresp were more suppressible by approximately 30% than their memory counterparts. This suggests that Treg cells may be more efficacious if administered before or at the time of transplantation and that depleting therapy should be avoided in clinical trials of Treg cells. This study describes lower suppressive capability of human regulatory T cells on autologous responder cells, which is of relevance to the design of clinical trials of cell therapy for the induction of tolerance to transplanted tissues.