How to Get from IgM to IgG

Abstract

Antibody-producing cells undergo a process of differentiation and class switch recombination (CSR) such that the antibodies produced start as immunoglobulin M (IgM) and then switch to IgG and IgA as the concentration of antigen changes and as the cells differentiate. Omori et al . show that CSR in antibody-secreting cells is inhibited in mice in which the lipid phosphatase pten gene has been selectively inactivated in B cells (b Pten −/− ). Flow cytometry analysis of splenocytes from immunized mice showed that the b Pten −/− mice formed germinal centers (sites of B cell differentiation) but did not exhibit the class switch from IgM-producing cells to IgG-producing cells that was observed for the wild-type mice. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) nonselectively, or of the PI3Kδ isoform selectively, resulted in enhanced production of IgG antibodies from wild-type mice and restored the production of IgG antibodies from the b Pten −/− cells. Inhibition of PI3Kδ allowed the wild-type cells to undergo CSR after the first cell division after exposure to antigenic stimulation, whereas in the absence of any inhibitors, the wild-type cells required at least three cell divisions before CSR was observed. Retroviral expression of constitutively active Akt also blocked CSR, and forced expression of nuclear-targeted Foxo1 transcription factor, the activity of which is inhibited by Akt, promoted CSR. Thus, PI3Kδ signaling through the Akt to inhibit Foxo1 appears to be required for inhibition of CSR. Indeed, the expression of the gene encoding activation-induced cytidine deaminase (AID), which is required for CSR, was decreased in cells expressing the constitutively active Akt. The authors suggest that when antigenic load is high, the activity of PI3K is high and CSR is inhibited to allow the IgM-producing cells to promote initial clearance of the antigen. As antigenic load decreases, PI3K stimulation also decreases, allowing CSR and the formation of specialized B cells producing different antibody isotypes. S. A. Omori, M. H. Cato, A. Anzelon-Mills, K. D. Puri, M. Shapiro-Shelef, K. Calame, R. C. Rickert, Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity 25 , 545-557 (2006). [PubMed]