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 Igha/a mice are able in vivo to totally and chronically inhibit the production of IgG2ab (IgG2a from the Ighb haplotype). Accordingly, postnatal transfer of Igha/a T splenocytes into histocompatible Igha/b F1 or congenic Ighb/b mice leads to a characteristic IgG2ab suppression. The helper action of anti-IgG2ab CD4+ T cells is required for the recruitment of anti-IgG2ab 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 IgG2ab production. In the present study we first showed that in vivo agonistic anti-CD40 mAb treatment of Igha/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 IgG2ab 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, Igha/a Pfp°/° T cells (using exclusively the Fas pathway) induced full IgG2ab suppression against Ighb/b CD40+/+ B cells, but only partial inhibition of IgG2ab production against Ighb/b CD40°/° 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.