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

Abstract

To investigate the possible role of CD40 in a negative regulation of Ig production, we used the mouse Ig allotype suppression model. T splenocytes from IGH(a/a) mice are able in vivo to totally and chronically inhibit the production of IgG(2a)(b) (IgG2a from the IGH(b) haplotype). Accordingly, postnatal transfer of IGH(a/a) T splenocytes into histocompatible IGH(a/b) F(1) or 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 recruitment of anti-IgG(2a)(b) CD8(+) T suppression effectors. The latter use perforin (pore-forming protein, Pfp)- and/or Fas-dependent cytotoxic pathways to continuously eliminate B cells recently committed to IgG(2a)(b) production. In the present study we first showed that in vivo agonistic anti-CD40 mAb treatment of IGH(a/a) mice, deprived of their CD4(+) T cell compartment, could bypass the help of Ig allotype-specific CD4(+) T cells and generate 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-effector mechanism, we demonstrated that B cell CD40 expression was required for full suppression establishment via the Fas-dependent pathway. Indeed, IGH(a/a) PFP(degrees/degrees) T cells (using exclusively the Fas pathway) induced full IgG(2a)(b) suppression against IGH(b/b) CD40(+/+) B cells, but only partial inhibition of IgG(2a)(b) production against IGH(b/b) CD40(degrees/degrees) B cells. This finding provides the first demonstration of direct involvement of B cell CD40 expression in in vivo negative control of an Ig production.