Controlling the Generation and Function of Human CD8+ Memory T Cells In Vitro with Immunosuppressants

Abstract

Memory T cells play a pivotal role in acute and chronic rejection of transplanted organs. Novel therapies such as alemtuzumab and the identification of heterologous memory have highlighted their importance following transplantation. Unlike naive T cells, the influence of immunosuppressive agents on the de novo generation of memory T cells and on the function of pre-existing memory T cells is poorly understood. CD8 effector memory T cells (Tem, CD45RA, CCR7) were generated by stimulating peripheral blood mononuclear cells for five days with anti-CD3 and anti-CD28 monoclonal antibodies, followed by nine days of rest. The influence of immunosuppression on this was assessed by flow cytometry. Tem that had been naturally formed in vivo were used to study the influence of the same agents on the function (intracellular interferon-gamma production) of Tem cells. Whereas all the immunosuppressive agents tested inhibited the expansion of CD8 Tem population by influencing their proliferation and apoptosis, the calcineurin inhibitors were better at controlling their function. Furthermore, Tem generated despite the presence of tacrolimus were functional and did not exhibit drug resistance. Immunosuppressive agents differ in their ability to control the generation and function of CD8 Tem; the calcineurin inhibitors being the most efficacious. This may be of importance when tailoring immunosuppressants for transplant recipients, particularly in those where there is pre-existing immunological memory or in those receiving T-cell depleting therapies, which skews the immune repertoire towards memory.