Relative Resistance of Human CD4+ Memory T Cells to Suppression by CD4+CD25+ Regulatory T Cells: Memory Cells as Barriers to Treg-Cell Therapy

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.