Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in diabetes-prone nonobese diabetic mice and lupus-prone MRL-Fas(lpr) mice

• Published in: The Journal of immunology (1950) Vol. 172; no. 7; p. 4624
• Main Authors: Robey, Ian F, Peterson, Melissa, Horwitz, Marc S, Kono, Dwight H, Stratmann, Thomas, Theofilopoulos, Argyrios N, Sarvetnick, Nora, Teyton, Luc, Feeney, Ann J
• Format: Journal Article
• Language: English
• Published: United States 01.04.2004
• Subjects: Animals; Animals, Newborn; Autoimmune Diseases - genetics; Autoimmune Diseases - mortality; Autoimmune Diseases - pathology; Autoimmune Diseases - prevention & control; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Clone Cells; Crosses, Genetic; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - mortality; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - prevention & control; DNA Nucleotidylexotransferase - deficiency; DNA Nucleotidylexotransferase - genetics; DNA Nucleotidylexotransferase - physiology; fas Receptor - genetics; Female; Islets of Langerhans - pathology; Male; Mice; Mice, Inbred MRL lpr; Mice, Inbred NOD; Mice, Knockout; Receptors, Interleukin-2 - biosynthesis; Survival Analysis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 0022-1767
• DOI: 10.4049/jimmunol.172.7.4624

The wide diversity of the T and B Ag receptor repertoires becomes even more extensive postneonatally due to the activity of TdT, which adds nontemplated N nucleotides to Ig and TCR coding ends during V(D)J recombination. In addition, complementarity-determining region 3 sequences formed in the absence of TdT are more uniform due to the use of short sequence homologies between the V, D, and J genes. Thus, the action of TdT produces an adult repertoire that is both different from, and much larger than, the repertoire of the neonate. We have generated TdT-deficient nonobese diabetic (NOD) and MRL-Fas(lpr) mice, and observed a decrease in the incidence of autoimmune disease, including absence of diabetes and decreased pancreatic infiltration in NOD TdT(-/-) mice, and reduced glomerulonephritis and increased life span in MRL-Fas(lpr) TdT(-/-) mice. Using tetramer staining, TdT(-/-) and TdT(+/+) NOD mice showed similar frequencies of the diabetogenic BDC 2.5 CD4(+) T cells. We found no increase in CD4(+)CD25(+) regulatory T cells in NOD TdT(-/-) mice. Thus, TdT deficiency ameliorates the severity of disease in both lupus and diabetes, two very disparate autoimmune diseases that affect different organs, with damage conducted by different effector cell types. The neonatal repertoire appears to be deficient in autoreactive T and/or B cells with high enough affinities to induce end-stage disease. We suggest that the paucity of autoreactive specificities created in the N region-lacking repertoire, and the resultant protection afforded to the newborn, may be the reason that TdT expression is delayed in ontogeny.