Differentiation of regulatory T cells 1 is induced by CD2 costimulation

Induction and maintenance of peripheral tolerance is an important phenomeno n for the control of homeostasis in the immune system. There is now compell ing evidence for CD4(+) T cells that prevent immune pathology, both in auto immunity and in transplantation. However, the mechanisms involved in the sp ecific differentiation of these T cells are unknown. We had previously show n that repetitive stimulations of naive T cells in the presence of IL-10 in duce the differentiation of T regulatory cells 1. We further dissected the mechanism of IL-10 function and demonstrated that IL-10 acts by the down-re gulation of most costimulatory molecules without modifying the expression o f CD58. Using artificial APCs expressing various costimulatory molecules, w e demonstrated that, in contrast to other costimulation patterns, costimula tion via CD2 alone, in the absence of costimulations through CD28- or LFA-1 , induced T cell anergy in an IL-10-independent pathway along with the diff erentiation of Ag-specific regulatory T cells. T regulatory cell-1 differen tiation via CD2 was very efficient as both high IL-10 secretion and regulat ory function were observed after the first stimulation of naive T cells wit h CD32-CD58 L cells. The possibility to rapidly induce the differentiation of Ag-specific regulatory T cells will certainly accelerate their character ization and their potential use as regulators of T cell-mediated diseases.