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

Successful expansion of functional CD4(+) CD25(+) regulatory T cells (T-reg) ex vivo under good manufacturing practice conditions has made T-reg-cell therapy in clinical transplant tolerance induction a feasible possibility. In animals, T-reg 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 naive 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 T-reg cells are less suppressive on memory, compared with naive Tresp that mediate allograft rejection. As a result, in the context of human T-reg-cell therapy, it is important to define the effectiveness of Treg cells in regulating naive and memory Tresp. Therefore, we compared suppression of peripheral blood naive and memory Tresp by fresh and ex vivo expanded T-reg cells using proliferation, cytokine production and activation marker expression (CD154) as readouts. With all readouts, naive human Tresp were more suppressible by approximately 30% than their memory counterparts. This suggests that T-reg 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 T-reg cells.