Effect of Different Therapeutic Strategies on Regulatory T Cells in Kidney Transplantation: a Randomized Study

Immune response is mediated by the interaction between antigen-presenting cells (APC), CD4+ helper T cells (Th) and regulatory T cells (Treg), a subpopulation of CD4+ T cells which intensively expresses IL-2 receptor (CD25) and FoxP3 transcription factor. Treg cells contribute maintaining tolerance by suppressing immune response to normal or tumour self-antigens. Treg cells originate in the thymus during ontogenesis and represent approximately 10% of peripheral CD4+ cells. All effector T lymphocytes generate in the thymus at the early stages of life and evolve through the production of new T lymphocytes as well as through antigen-induced expansion of virgin (naive) peripheral T lymphocytes which convert to "memory" T lymphocytes and lie in peripheral lymphoid organs (17). Mature T lymphocytes constitute 70-80% of normal peripheral blood lymphocytes, 30-40% of lymph nodes cells and 20-30% of splenic lymphoid cells.

T lymphocytes are primary effectors of cell-mediated immunity and differentiate into a subpopulation of CD8+ cytotoxic T lymphocytes which are able to lyse foreign cells or virus infected host-cells and a subpopulation of CD4+ T lymphocytes with a regulating activity on T and B lymphocytes and monocytes, through the production of cytokines and cell-to-cell contact.

Treg lymphocytes play a central role among CD4+ cells in balancing tolerance and immunity, as they are responsible for maintaining peripheral tolerance through the control of self-reactive T cells which escaped thymic deletion (19). Studies have in fact demonstrated that whether on one side a defect in their development or activity can lead to serious autoimmune diseases, an excessive immunosuppression mediated by these cells stimulates, on the other side, an immunodeficient condition also towards antigens produced by neoplastic cells favouring, as a consequence, tumour growth.

Treg lymphocytes represent approximately 10% of all CD4+ T cells present in the thymus, peripheral blood and lymphoid tissues; they consist of various populations which differ in terms of particular cell-surface molecules expression and the production of diverse cytokines, but share a common scarce response to antigenic stimulation and an immunosuppressive activity.

The best characterized Treg lymphocytes are the so called "natural occurring Tregs" (nTregs), a sub-group of CD4+ T cells which originates and develops in the thymus during T-cellular maturation process and is afterwards normally present in peripheral blood with the function of controlling self-antigens and preventing autoimmune diseases. These lymphocytes are characterized by the constitutive expression of CD-25 (interleukin-2 receptor α chain), Foxp3 transcription factor (specific to these cells and implied in the development control within the thymus), CTLA-4, GITR and LAG-3 surface molecules as well as TGF-β cytokine, which is present in great quantity on cellular surface and is fundamental to their functioning.