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.

Significant alterations of biodistribution and immune responses in Balb/c mice administered with adenovirus targeted to CD40(+) cells

“…There are previous reports documenting that CD40 ligation could lead to largely positive growth outcomes for resting B cells, but inhibited the growth and Ig production of activated B cells which are also known to be CD40(+). 39,[51][52][53] Given these findings, caution appears to be warranted when considering CD40L as targeting moiety for adenoviral vectors in genetic immunization when induction of humoral immune response is crucial, that is, neutralizing antibodies against pathogens. Nevertheless, therapeutic manipulation to facilitate biased or skewed immune responses could be beneficial in clinical applications.…”