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

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-body^3–5 and deposition of immune complexes in the thymus, skin, lungs and kidneys^1,3. 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 B^9,10 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.