The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/8/483/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 3, August 3, 1998 483-495

Articles

Regulation of B Cell Development by Variable Gene Complexity in Mice Reconstituted with Human Immunoglobulin Yeast Artificial Chromosomes

Larry L. Green and Aya Jakobovits

From Abgenix, Inc., Fremont, California 94555

The relationship between variable (V) gene complexity and the efficiency of B cell development was studied in strains of mice deficient in mouse antibody production and engineered with yeast artificial chromosomes (YACs) containing different sized fragments of the human heavy (H) chain and {kappa} light (L) chain loci. Each of the two H and the two {kappa} chain fragments encompasses, in germline configuration, the same core variable and constant regions but contains different numbers of unique VH (5 versus 66) or V{kappa} genes (3 versus 32). Although each of these YACs was able to substitute for its respective inactivated murine counterpart to induce B cell development and to support production of human immunoglobulins (Igs), major differences in the efficiency of B cell development were detected. Whereas the YACs with great V gene complexity restored efficient development throughout all the different recombination and expression stages, the YACs with limited V gene repertoire exhibited inefficient differentiation with significant blocks at critical stages of B cell development in the bone marrow and peripheral lymphoid tissues. Our analysis identified four key checkpoints regulated by VH and V{kappa} gene complexity: (a) production of functional µ chains at the transition from the pre B-I to the pre B-II stage; (b) productive V{kappa}J{kappa} recombination at the small pre B-II stage; (c) formation of surface Ig molecules through pairing of µ chains with L chains; and (d) maturation of B cells. These findings demonstrate that V gene complexity is essential not only for production of a diverse repertoire of antigen-specific antibodies but also for efficient development of the B cell lineage.

Key Words: B cell development • human immunoglobulin • variable genes • transgenic mice • yeast artificial chromosomes

Address correspondence to Aya Jakobovits, Abgenix, Inc., 7601 Dumbarton Circle, Fremont, CA 94555. Phone: 510-608-6599; Fax: 510-608-6511; E-mail: jakobovits_a{at}abgenix.com

Abbreviations used: BCR, B cell receptor; h, human; m, mouse; RAG, recombination activating gene; sIg, surface immunoglobulin; SLC, surrogate light chain(s); TG, rearranged µ chain transgene; YAC, yeast artificial chromosome.


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