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.

Reversible lacrimal gland‐protective regulatory T‐cell dysfunction underlies male‐specific autoimmune dacryoadenitis in the non‐obese diabetic mouse model of Sjögren syndrome

“…24,28,29 How such global defects would result in organ-specific autoimmunity is not entirely clear and would require an additional organ-specific modifying factor. Defects in NOD Treg cell thymic development have also been reported, including decreased diversity of the Treg TCR repertoire, 25,30,31 which may lead to holes in antigen-specific Treg populations and subsequent increased susceptibility to organ-specific autoimmunity. Our results do not support a complete lack of lacrimal gland-protective Treg cells in male NOD mice given that male cervical LN-derived Treg cells are capable of preventing the transfer of dacryoadenitis to female recipients.…”

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

“…This selection defect in NOD mice was recently mapped to the same genetic locus (Idd9) that controls the attenuation of the ERK signaling module in NOD T cells (6). Altogether, these observations suggest that the impaired activation of the ERK signaling module and the decreased diversity of the Treg repertoire in Phosphorylation differential between Erk2-deficient and -sufficient mice averaged across two independent series.…”

“…This phenotype was caused by a selective defect in ERK1/2 activation downstream of the TCR, which is apparently an isolated defect, because calcium mobilization and general phosphotyrosine activation seemed normal in activated NOD T cells (5). This defect in ERK phosphorylation on TCR engagement was recently confirmed by an independent study (6), and it manifests at all stages of T-cell differentiation from early thymic pre-T cells to mature T cells in peripheral organs.…”

Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes

“…However, recent work suggest that differences between diabetes-prone NOD mice and other mice strains may reside in Treg function. Mechanisms, including age-related decline of transforming growth factor (TGF)-β production (Gregg et al 2004), interleukin (IL)-2 insufficiency (Yamanouchi et al 2007), resistance of effector T cells to regulation (D'Alise et al 2008), or an unusually reduced TCR diversity (Ferreira et al 2014), are often cited to explain these differences in animal models.…”