The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors.
FoxP3(+) regulatory T cells (Tregs) protect against autoimmunity, type 1 diabetes (T1D) in particular, prompting the hypothesis that a deficiency in Tregs is a critical determinant of diabetes susceptibility in NOD mice. However, tests of this hypothesis have yielded contradictory results. We confirmed that NOD mice, compared with reference strains, do not have a primary deficit in Treg numbers in the lymphoid organs, whether in prediabetic mice of any age or in animals with recent-onset diabetes. NOD Tregs did show a defect in standard in vitro T cell suppression assays, particularly at low suppressor/effector ratios. Gene expression profiling revealed the vast majority of transcripts constituting the "Treg signature" to be normally distributed in NOD Tregs versus CD4(+) T conventional (Tconv) cells, although there were a few differences affecting one or the other population. According to results from criss-cross experiments, the functional inefficacy was not rooted in NOD Tregs, which suppressed as well as their C57BL/6 (B6) counterparts, but rather in NOD Tconv, which were less prone to suppression than were B6 Tconv cells. They also responded more effectively to anti-CD3/28 monoclonal antibody (mAb) stimulation in vitro or to a natural pancreatic antigen in vivo. This difference was independent of autoimmune inflammation, did not map to the idd3 region, and was not due to the overproduction of interleukin-21 in NOD mice. That the immune dysregulation in this T1D model is rooted in the ability of effector T cells to be regulated, rather than in Tregs themselves, has implications for proposed therapeutic interventions.
D'Alise
Anna Morena
AM
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Auyeung
Vincent
V
Feuerer
Markus
M
Nishio
Junko
J
Fontenot
Jason
J
Benoist
Christophe
C
Mathis
Diane
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D018791:CD4 Lymphocyte Count; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000276:immunology; D020869:Gene Expression Profiling; D051379:Mice; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000037:antagonists & inhibitors / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7