Terminal deoxynucleotidyl transferase deficiency reduces the incidence of autoimmune nephritis in (New Zealand Black x New Zealand White)F-1 mice

Terminal deoxynucleotidyl transferase (TdT) enzyme activity in lymphocytes generates diversity in the Ag receptor repertoires by adding template-indep endent N nucleotides and disrupting homology-directed rearrangements. The i mportance of this diversity in vivo and the significance of the suppression of TdT during fetal life remain uncertain, Previous studies have shown tha t in TdT knockout mice (TdT degrees) 1) the T cell repertoire is less pepti de oriented; and 2) natural autoantibody, particularly anti-DNA autoantibod ies, are less polyreactive, and their mean affinities are reduced. Conseque ntly, the suppression of TdT during early T/B cell ontogeny may participate in controlling autoimmunity. To study the impact of TdT suppression in aut oimmune-prone mice, we introduced the TdT null mutation into the (NZB x NZW )F-1 (B/W) mouse strain, We show that TdT deficiency significantly reduces the incidence of autoimmune nephritis and prolongs survival compared with t hose in control mice. Surprisingly, the long-term survivor TdT degrees mice produced amounts of anti-ADN and anti-histone autoantibodies similar to th ose of their TdT(+) littermates. However, these TdT degrees mice showed no evidence of renal inflammation, and the immune deposits were restricted to the mesangium, whereas basal membrane deposits were clearly correlated with overt renal disease. The present study supports the idea that the absence of TdT enzyme activity in lymphocytes protects mice against autoimmunity an d could offer a therapeutic approach to autoimmune diseases. Moreover, our results may help to unravel the mechanisms of lupus nephritis.