Idd13 is involved in determining immunoregulatory DN T-cell number in NOD mice

Abstract

Immunoregulatory T cells have been identified as key modulators of peripheral tolerance and participate in preventing autoimmune diseases. CD4(-)CD8(-) (double negative, DN) T cells compose one of these immunoregulatory T-cell subsets, where the injection of DN T cells confers protection from autoimmune diabetes progression. Interestingly, genetic loci defining the function and number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) coincide with at least some autoimmune disease susceptibility loci. Herein, we investigate the impact of major insulin-dependent diabetes (Idd) loci in defining the number of DN T cells. We demonstrate that although Idd3, Idd5 and Idd9 loci do not regulate DN T-cell number, NOD mice congenic for diabetes resistance alleles at the Idd13 locus show a partial restoration in DN T-cell number. Moreover, competitive and non-competitive bone marrow chimera experiments reveal that DN T-cell number is defined by a bone marrow-intrinsic, but DN T-cell-extrinsic, factor. This suggests that non-autonomous candidate genes define DN T-cell number in secondary lymphoid organs. Together, our results show that the regulation of DN T-cell number in NOD mice is at least partially conferred by alleles at the Idd13 locus.

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

“…1B). In agreement with our previous finding that the Idd13 locus only partially restores DN T cell proportion in NOD mice (24), the normal distribution suggests that more than one locus contributes toward defining the proportion of 3A9 DN T cells in the lymph nodes.…”

“…Specifically, autoimmune-prone mice carry fewer DN T cells, and injection of DN T cells has been shown to be sufficient to reduce the incidence of autoimmune diabetes in two distinct TCR transgenic mouse models (21,22). Importantly, a low DN T cell proportion, rather than defects in DN T cell function, associates with diabetes susceptibility (22)(23)(24). Together, these observations suggest that variations in DN T cell proportion correlate with susceptibility to autoimmune diabetes.…”

“…We establish that the proportion of DN T cells is a complex trait, where the locus exhibiting the highest logarithm of odds (LOD) score is located on chromosome 9 and coincides with the Idd2 locus. In line with our previous findings, the distal region of chromosome 2, which encompasses the Idd13 locus, also shows a suggestive linkage to 3A9 DN T cell proportion (24). We develop congenic mice to validate the contribution of the chromosome 9 locus in defining the proportion of DN T cells in peripheral lymphoid organs and explore the role of this locus in conferring resistance to autoimmune diabetes.…”

“…Because of these challenges, we instead opted to take advantage of the 3A9 TCR transgenic mouse model, in which the TCR recognizes a peptide from HEL in the context of I-A k (29), allowing to investigate the genetic regulation of the proportion of DN T cells in secondary lymphoid organs. Indeed, as for other TCR transgenic systems (15,(38)(39)(40)(41)(42)(43), the 3A9 TCR transgenes enhance the proportion of DN T cells in peripheral lymphoid organs and preclude the differentiation of potentially contaminating NKT cells, increasing the sensitivity of detection of DN T cells (22)(23)(24). We thus performed an F2 out- cross of the 3A9 TCR B10.BR and 3A9 TCR NOD.H2 k parental strains, because they exhibit a significant difference in the proportion of 3A9 DN T cells in the lymph nodes (22 k ) mice varies from 5 to 34% and presents with a Gaussian distribution (Fig.…”

“…In addition, NOD congenic mice have proved useful in defining genetic loci linked to autoimmune diabetes susceptibility (27). To that effect, we have recently shown that the NOD.NOR-Idd13 congenic mice, which are resistant to diabetes progression (28), show a modest increase in DN T cell number relative to NOD mice, but that neither Idd3, Idd5, nor Idd9 con-tribute to this trait (24). Notably, the genetic determinants from the Idd13 locus only partially restored DN T cell number, strongly suggesting that other genetic loci also contribute toward defining the proportion of DN T cells.…”