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Role of CD40 in a T Cell-Mediated Negative Regulation of Ig Production¹

Unité d’Immunophysiologie Moléculaire, Institut Pasteur, Paris, France

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 F₁ 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^°/° 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^°/° 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.