B Cell Antigen Receptor-intrinsic Costimulation of IgG and IgE Isotypes

Abstract

B cells express different isotypes of the B cell antigen receptor (BCR) on their surface and secrete soluble forms of their antigen binding immunoglobulins (Ig) upon differentiation to plasma cells. Naïve mature B cells use Ig heavy chains of the µ and δ isotypes while antigen-experienced cells change the isotype to either α, γ and ε during an ongoing immune response, a process called Ig class-switch recombination. The change of isotype alters the effector function of the respective secreted immunoglobulin while preserving its antigen specificity. The humoral immune response upon first encounter of an antigen is therefore characterized by the secretion of immunoglobulin M (IgM), while antibodies of class-switched isotypes are secreted upon secondary encounter of the same antigen, with IgG being the predominant isoform. Moreover, the secondary immune response is much more rapid and vigorous, which is based on the fast reactivation, proliferation and differentiation of memory B cells into plasma cells. B cell activation during primary and secondary immune responses relies on signals through the BCR. Both, naïve and Ig class-switched B cells use the canonical BCR pathway initiated by the Ig-associated Igα/β heterodimer. Signaling through mIgM- and mIgD-BCRs is completely dependent on the Igα/β heterodimer as both Igs only contain cytoplasmic parts of three amino acids. However, mIgG and mIgE heavy chains both contain cytoplasmic tails of 28 amino acids that has been shown to be essential for mounting robust secondary immune responses (Achatz et al., 1997; Kaisho et al., 1997). The molecular mechanisms of this enhanced signaling remained completely elusive. The work presented show that a conserved tyrosine residue within these cytoplasmic tails, entitled the immunoglobulin tail tyrosine (ITT), is phosphorylated upon BCR stimulation and amplifies BCR-induced Ca2+ mobilization by the recruitment of Grb2 (Engels et al., 2009). The enhanced signaling through IgG- and IgE-BCRs in fact culminates in a prolifera tive burst that is one hallmark of the memory B cell response. Recruitment of Grb2 engaged additional or stabilized existing protein complexes of the BCR signalosome. Thus, by Ig class-switching B cells not only alter the effector function of the respective secreted antibody but also add another signaling motif to the BCR providing receptor-intrinsic “costimulation”.