Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in "human immune system" Rag2(-/-)gammac(-/-) mice

Efficient and quick reconstitution of T-cell compartments in lymphopenic patients is of great importance to prevent opportunistic infections, but remains difficult to achieve. Human T-cell proliferation in a T-cell-receptor (TCR)-independent manner is possible in vitro with superagonist anti-CD28 antibodies, and such molecules are therefore promising therapeutic tools. Here, we investigated the in vivo effects of superagonist anti-CD28 treatment on human developing and mature T cells, in the recently developed model of "human immune system" BALB/c Rag2(-/-)gammac(-/-) mice. Our results show that superagonist anti-CD28 treatment transiently induces a 7-fold increase in thymocyte numbers and up to 18-fold accumulation of mature thymocytes. The increased thymic production lead to transient accumulation of mature T cells in the periphery at the peak of treatment effect (day 6). In addition, long-term peripheral T-cell depletion was induced. Furthermore, the concomitant selective expansion and accumulation of suppressive CD4+CD25+FoxP3+ T cells was induced in a transient manner. Superagonist anti-CD28 therapy could therefore be of clinical interest in humans, both for beneficial effect on thymic T-cell production as well as regulatory T-cell accumulation