title: Reduced regulatory T cell diversity in NOD mice is linked to early events in the thymus.
abstract: The thymic natural regulatory T cell (Treg) compartment of NOD mice is unusual in having reduced TCR diversity despite normal cellularity. In this study, we show that this phenotype is attributable to perturbations in early and late stages of thymocyte development and is controlled, at least in part, by the NOD Idd9 region on chromosome 4. Progression from double negative 1 to double negative 2 stage thymocytes in NOD mice is inefficient; however, this defect is compensated by increased proliferation of natural Tregs (nTregs) within the single positive CD4 thymocyte compartment, accounting for recovery of cellularity accompanied by loss of TCR diversity. This region also underlies the known attenuation of ERK-MAPK signaling, which may preferentially disadvantage nTreg selection. Interestingly, the same genetic region also regulates the rate of thymic involution that is accelerated in NOD mice. These findings highlight further complexity in the control of nTreg repertoire diversity.
authors.affiliation: Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferreira
authors.forename: Donald
authors.initials: D
authors.lastname: Palmer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Blake
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Garden
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005434:Flow Cytometry; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*