The most debilitating human lymphoid deficiency disease, known as severe combined immunodeficiency (SCID), impairs the differentiation of both T and B lymphocytes. Affected infants are highly susceptible to recurring infections of viruses, fungi and bacteria and invariably die within 2 yr of birth. Inheritance of this congenital syndrome may show X-linked or autosomal recessive control. To date autosomal recessive inheritance of SCID has been observed in Arabian foals which represent the only known animal model of this disease syndrome but here we report an autosomal recessive mutation in mice that severely impairs lymphopoiesis. Mice homozygous for this mutation have few if any lymphocytes; consequently they are hypogammaglobulinaemic and deficient for immune functions mediated by T and B lymphocytes. These mice, therefore, represent a new model for investigating how lymphoid differentiation may be impaired in the disease state and regulated in the normal state.

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Lymphoid and myeloid cells represent distinct lineages of a common hematopoietic stem cell (1-3). This distinction is dramatically illustrated in the autosomal recessive mouse mutant, scid . t Mice homozygous for the scid mutation (scid mice) are severely deficient in B and T lymphocytes whereas other hematopoietic cell types such as erythrocytes, monocytes, granulocytes, and megakaryocytes (all members of the myeloid series) are present in normal number (4, 5). Although the scid mutation appears to affect only lymphocyte development (4-10), it is not yet clear what stage of lymphoid differentiation is impaired or arrested .Recent results suggest that the effects of the scid mutation become manifest after the commitment of lymphoid cells to the B and T cell pathways . First, early transcription of unrearranged H chain and TCR loci, which presumably signals the opening of these loci to factors responsible for gene recombination (11-16), is detectable in scid fetal liver and thymus, respectively (Schuler, W., A. Schuler, and M. J. Bosma, unpublished results) . Second, although cells with H chain (or TCR) gene rearrangements cannot be directly demonstrated in freshly harvested lymphoid tissues of adult scid mice (17), early B cell lines with H chain gene rearrangements can be recovered from Abelson murine leukemia virus-transformed scid bone marrow cells (17) and from long-term cultures of scid bone marrow cells (18). There is also indication of early T cell development as thymic lymphomas with rearranged TCR-'Y and TCR-# alleles spontaneously appear in -15% of scid mice (5,17,19). It is striking, however, that the majority of rearranged H chain and TCR alleles in transformed scid lymphocytes show abnormal J region deletions. The deletions remove all J-coding exons of a given J region and appear to result from attempted D to J or V to Jjoining; they vary in size and extend both 5' and 3' of the deleted J regions (17,19). Evidence of abnormal J-associated deletions has also been reported for rearranged H chain alleles of long-term B cell lines derived from scid bone marrow cells (18).To explain the abnormal J-associated deletions and how they might account

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Mice homozygous for the scid mutation (scid mice) are severely deficient in functional B and T lymphocytes. The mutation appears to impair the recombination of antigen receptor genes and thereby causes an arrest in the early development of B and T lineage-committed cells; other hematopoietic cell types appear to develop and function normally. The arrest in lymphocyte development is not absolute; some young adult scid mice are "leaky" and generate a few clones of functional B and T cells. By 10-14 months of age, virtually all scid mice are leaky. Scid mice readily support normal lymphocyte differentiation and can be reconstituted with normal lymphocytes from other mice and even partially reconstituted with human lymphocytes. They also support the growth of allogeneic and xenogeneic tumors. Thus, scid mice are of interest for studies of both normal and abnormal lymphocyte development and function. In addition, they can be used to study the function of nonlymphoid cell types in the absence of lymphocytes.

Class switch recombination (CSR), similar to V(D)J recombination, is thought to involve DNA double strand breaks and repair by the nonhomologous end–joining pathway. A key component of this pathway is DNA-dependent protein kinase (DNA-PK), consisting of a catalytic subunit (DNA-PKcs) and a DNA-binding heterodimer (Ku70/80). To test whether DNA-PKcs activity is essential for CSR, we examined whether IgM+ B cells from scid mice with site-directed H and L chain transgenes were able to undergo CSR. Although B cells from these mice were shown to lack DNA-PKcs activity, they were able to switch from IgM to IgG or IgA with close to the same efficiency as B cells from control transgenic and nontransgenic scid/+ mice, heterozygous for the scid mutation. We conclude that CSR, unlike V(D)J recombination, can readily occur in the absence of DNA-PKcs activity. We suggest nonhomologous end joining may not be the (primary or only) mechanism used to repair DNA breaks during CSR.