Role of CD40 in a T cell-mediated negative regulation of Ig production

To investigate the possible role of CD40 in a negative regulation of Ig pro duction, we used the mouse Ig allotype suppression model, T splenocytes fro m Igh(a/a) mice are able in vivo to totally and chronically inhibit the pro duction of IgG(2a)(b) (IgG2a from the Igh(b) haplotype). Accordingly, postn atal transfer of Igh(a/a) T splenocytes into histocompatible Igh(a/b) F-1 o r congenic Igh(b/b) mice leads to a characteristic IgG(2a)(b) suppression. The helper action of anti-IgG(2a)(b) CD4(+) T cells is required for the rec ruitment of anti-IgG(2a)(b) CD8(+) T suppression effectors. The latter use perforin (pore-forming protein, Pfp)- and/or Fas-dependent cytotoxic pathwa ys to continuously eliminate B cells recently committed to IgG(2a)(b) produ ction. In the present study we first showed that in vivo agonistic anti-CD4 0 mAb treatment of Igh(a/a) mice, deprived of their CD4(+) T cell compartme nt, could bypass the help of Ig allotype-specific CD4(+) T cells and genera te CD8(+) T effector cells able to strongly inhibit IgG(2a)(b) production. This result demonstrates the usefulness of CD40 triggering in setting up an immune regulatory mechanism. Furthermore, with regard to the suppression-e ffector mechanism, we demonstrated that B cell CD40 expression was required for full suppression establishment via the Fas-dependent pathway. Indeed, Igh(a/a) Pf(o/o) T cells (using exclusively the Fas pathway) induced full I gG(2a)(b) suppression against Igh(b/b) CD40(+/+) B cells, but only partial inhibition of IgG(2a)(b) production against Igh(b/b) CD40(o/o) B cells. Thi s finding provides the first demonstration of direct involvement of B cell CD40 expression in in vivo negative control of an Ig production.