ICOS is critical for CD40-mediated antibody class switching

The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation(1-5). Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimu latory signals may enable the design of rational therapies for immune-media ted diseases(6). According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, sig nal for optimal T-cell activation(6). The co-stimulatory signal promotes T- cell proliferation, lymphokine secretion and effector function. The B7-CD28 pathway provides essential signals for T-cell activation, but does not acc ount for all co-stimulation. We have generated mice lacking ICOS (ICOS-/-) to determine the essential functions of ICOS. Here we report that ICOS-/- m ice exhibit profound deficits in immunoglobulin isotype class switching, ac companied by impaired germinal centre formation. Class switching was restor ed in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B -cell collaboration through the CD40/CD40L pathway.