CD28 blockade induces division-dependent downregulation of interleukin-2 receptor alpha

Blockade of T cell costimulatory molecules represents a promising new method of attenuating donor-reactive T cell responses to promote graft survival following transplantation. However, recent studies in murine models have shown the presence of an initial high frequency of naïve donor-reactive T cells may render this strategy ineffective.

In this report, we examined the phenotypic changes associated with CD28 blockade on T cells stimulated at increasing precursor frequencies in vitro.

We found that treatment with the CD28 blocker CTLA-4 Ig resulted in downregulation of the alpha chain of the IL-2 receptor (CD25) in a division-dependent manner. Significantly, blockade of the CD28 pathway was more effective in down-regulating CD25 when the donor-reactive T cell population was present at low as compared to high precursor frequency.

These results imply that treatment with CD28 blockers and anti-CD25 mAbs may cooperate in promoting graft survival under conditions of low MHC matching where the donor-reactive T cell precursor frequency is high.