FUNCTIONAL IMMUNOGLOBULIN TRANSGENES GUIDE ORDERED B-CELL DIFFERENTIATION IN RAG-1-DEFICIENT MICE

We have examined the regulatory role of the individual components of t he immunoglobulin antigen receptor in B-cell development by transgenic complementation of Rag-1 deficient (Rag-1(-)) mice. Complementation w ith a membrane mu heavy chain (mu HC) gene allows progression of devel opmentally arrested Rag-1(-) pro-B-cells to the small pre-B cell stage , whereas the introduction of independently integrated mu HC and kappa light chain (kappa LC) transgenes promotes the appearance of peripher al lymphocytes which, however, remain unresponsive to external stimuli . Complete reconstitution of the B-cell lineage and the emergence of f unctionally mature Rag-1(-) peripheral B cells is achieved by the intr oduction of cointegrated heavy and light chain transgenes encoding an anti-H-2(k) antibody. This experimental system demonstrates the compet ence of the mu HC and kappa LC to direct and regulate the sequential s tages of B cell differentiation, defines the time at which negative se lection of self-reactive B cells occurs, and shows that elimination of these cells occurs equally well in the absence of Rag-1 as in its pre sence. These data also support the hypothesis that Rag-1 directly part icipates in the V(D)J recombination process.