Models for the effects on mucosally induced tolerance of perturbing the CD40L-CD40 interaction. (a) In the untreated wild-type mouse, CD40 on dendritic cells (DCs) and other APCs interacts with CD40L expressed on T cells of several subsets, including CD4 and CD8 cells, as well as a CD25 CD4 population of regulatory T cells (Tr). This interaction can lead to both active, antigen-specific CTL responses and the suppression of Th function and inflammation. The latter effects appear to be implicated in mucosally induced tolerance to dietary antigens and endogenous bacteria. (b) As shown by Hänninen et al. in this issue of the JCI (8), transient treatment with mAb anti-CD40L can prevent induction of CTLs, while apparently leaving some of the other responses intact. Thus, mucosally induced tolerance is not compromised by this treatment. (c) In case of the permanent blockage of CD40L-CD40, as occurs in CD40L–/– mice, the additional loss of some immunosuppressive signaling cascade and/or of a population of Tr cells prevents mucosally induced tolerance.