The immunoglobulin (Ig)alpha and Igbeta cytoplasmic domains are independently sufficient to signal B cell maturation and activation in transgenic mice.

The B cell antigen receptor, composed of membrane immunoglobulin (Ig) sheathed by the Igalpha/Igbeta heterodimer plays a critical role in mediating B cell development and responses to antigen. The cytoplasmic tails of Igalpha and Igbeta differ substantially but have been well conserved in evolution. Transfection experiments have revealed that, while these tails share an esssential tyrosine-based activation motif (ITAM), they perform differently in some but not all assays and have been proposed to recruit distinct downstream effectors. We have created transgenic mouse lines expressing chimeric receptors comprising an IgM fused to the cytoplasmic domain of each of the sheath polypeptides. IgM/alpha and IgM/beta chimeras (but not an IgM/beta with mutant ITAM) are each independently sufficient to mediate allelic exclusion, rescue B cell development in gene-targeted Igmu- mice that lack endogenous antigen receptors, as well as signal for B7 upregulation. While the (IgM/alpha) x (IgM/beta) double-transgenic mouse revealed somewhat more efficient allelic exclusion, our data indicate that each of the sheath polypeptides is sufficient to mediate many of the essential functions of the B cell antigen receptor, even if the combination gives optimal activity.

The Ig kappa 3'-enhancer triggers gene expression in early B lymphocytes but its activity is enhanced on B cell activation.

Ig kappa gene expression is controlled by two enhancers, one located within the major intron (Ei) and the other located downstream of C kappa (E3'). Whereas loss of E3' has previously been shown to diminish kappa expression, we show here that a rearranged kappa transgene lacking Ei is well expressed, even at the pre-B cell stage. This suggests that E3' alone might be sufficient to give properly regulated transcription throughout B cell development. Indeed, we show that a transgene composed of a beta-globin reporter linked to E3' is expressed in a B cell-specific manner, becoming activated at the late pro-B to pre-B cell stage but with dramatically enhanced activity on B cell activation. Thus, E3' becomes active as a transcription enhancer at the stage when V kappa-J kappa rearrangement is being initiated and is sufficient to yield an expression pattern in a linked reporter gene similar to that of fully rearranged kappa genes.