Deficiency in cells expressing terminal transferase in autoimmune (motheaten) mice

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Abstract
The extensive breakdown of immune homeostasis in the motheaten mouse (me/me) has been ascribed to a single gene defect on chromosome 6 (ref. 1). These mice develop skin lesions within the first week of life, do not thrive, and die within the first 3–8 weeks2. There is severe hypergamma-globulinaemia3 with multiple species of circulating autoanti-body3–5 and deposition of immune complexes in the thymus, skin, lungs and kidneys1,3. A single gene defect producing such catastrophic results may provide an important model for understanding autoimmune phenomena. We report here a virtual absence of terminal deoxynucleotidyl transferase-positive (TdT+) cells in the bone marrow, thymus and spleen of motheaten mice. TdT is a DNA polymerase which has the unique capacity to polymerize nucleotides in the absence of template direction6. Although no in vivo biological function of this enzyme has been established, its unique appearance in the bone marrow and thymus of adult mammals and its in vitro biochemical activity6 have led to a proposed role for TdT in the somatic diversification of lymphocytes7. Bone marrow TdT+ cells have been shown to belong to both T8 and B9,10 cell populations and may also include precursor cells common to these lineages11. Although the role of TdT in the acquisition of appropriate T- and B-cell specificities is not known, our results are the first to correlate the virtual absence of TdT+ cells with a severe autoimmune syndrome. We investigated the level of TdT+ cells in neonatal me/me mice and their normal littermates and the susceptibility of TdT+ cells to circulating autoantibody in motheaten mouse serum.