Class switching in human immunoglobulin transgenic mice.

We have introduced human germline-configuration heavy and kappa light chain minilocus transgenes into mice that have been engineered so that their endogenous heavy and kappa light chain loci are inactive. The two human transgenes are inserted by pronuclear microinjection, while the two endogenous mouse genes are disrupted by homologous recombination in embryonic stem cells. The resulting animals contain four unlinked genetic modifications and must rely on the introduced transgenes for the development of the B-cell lineage and for the generation of an antibody repertoire. The heavy chain transgene includes both the human mu and the human gamma 1 constant region gene segments, as well as upstream switch region sequences. Although mouse B cells and human B cells exhibit species-specific differences in the induction of gamma isotype expression, the transgenic mouse B cells appear to undergo regulated switching to human gamma 1 both in vivo and in vitro. This observation defines a subset of the heavy chain constant region that is sufficient for class switching, and implies that the human gamma 1 switch region includes a core of sequence that is functionally homologous to those cis-acting regulatory elements that direct mouse gamma switching.