Agonistic anti-4-1BB antibody promotes the expansion of natural regulatory T cells while maintaining Foxp3 expression.

The engagement of the 4-1BB (CD137) co-stimulatory pathway promotes the activation and proliferation of conventional CD4(+) T and CD8(+) T cells, but the role of 4-1BB co-stimulation in CD4(+) CD25(+) regulatory T cells (Treg) is less clear. In particular, whether 4-1BB stimulation affects the expression of Foxp3, a master gene for Treg, is unknown. This study demonstrates that co-stimulation of 4-1BB engaged by an agonistic antibody promotes the proliferation of Treg in a dependent manner of low-concentration interleukin-2 in vitro. The 4-1BB-expanded Treg maintain Foxp3 expression and their ability to suppress conventional CD4(+) T cells and their feature to produce no interleukin-2. However, the 4-1BB-expanded Treg produce increased levels of interferon-gamma, whose significance is unknown. Thus, 4-1BB co-stimulation plays a role in the expansion of functional CD4(+) CD25(+) Treg cells without adversely affecting their suppressive activity.