Interleukin‐10 limits the expansion of immunoregulatory CD4⁻CD8⁻ T cells in autoimmune‐prone non‐obese diabetic mice

Abstract

Regulatory T cells appear to show great potential for use in cellular therapy. In particular, CD4 À CD8 À (double negative (DN)) T cells, which compose 1-3% of the total number of T lymphocytes, exhibit prominent antigen-specific immune tolerance properties and confer immune tolerance in models of allografts and xenografts. We have recently shown that autoimmunediabetes-prone mice carry fewer DN T cells and that this phenotype contributes to autoimmune-prone diabetes susceptibility, suggesting that increasing DN T-cell number in autoimmune-prone individuals may be of therapeutic interest. To achieve this goal, we must first determine whether the remaining DN T cells in autoimmune-prone mice are functional. In addition, we must identify the parameters that regulate the numbers of DN T cells. Herein, we evaluate the immunoregulatory properties of DN T cells in the autoimmune-prone non-obese diabetic (NOD) genetic background. Using 3A9 TCR transgenic mice, we show that DN T cells from both diabetes-resistant B10.Br and genetically autoimmune-prone NOD.H2 k mice show an equivalent immunoregulatory potential on a per cell basis. However, upon stimulation, there is a 10-fold increase in the number of 3A9 TCR transgenic DN T cells that produce interleukin10 (IL-10) from NOD.H2 k mice in comparison with B10.Br mice. We further showed that IL-10 facilitates DN T-cell apoptosis and thus may regulate the number of DN T cells. Taken together, our results show that, although reduced in number, DN T cells from mice carrying an autoimmune-prone genetic background exhibit a potent cytotoxic potential and that DN T-cell expansion is regulated, at least in part, by IL-10.

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

“…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.…”

“…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.…”

“…Indeed, regulatory DN T cells have been shown to promote allograft and xenograft tolerance (12)(13)(14)(15)(16)(17), limit the incidence of graft versus host disease (17)(18)(19)(20), as well as provide resistance to autoimmune diabetes development in different animal models (21)(22)(23). 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).…”

CD3+CD4−CD8− (double negative) T cells: Saviours or villains of the immune response?

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 NOD.H 2k but not in B10.Br control mice. They also showed that IL-10 produced by these cells favours their apoptosis and hence helps to regulate their number [75]. In another study by Duncan …”

Regulation of antigen‐expressing dendritic cells by double negative regulatory T cells

“…DN Tregs can suppress Ag-specific auto-, allo-or xeno-reactive CD8 1 [3,5,6], CD4 1 T cells [6][7][8][9] or B cells [10,11] in several animal models and humans. The number of DN Tregs is significantly reduced in both NOD mice as well as in TCR Tg autoimmunediabetes-prone mouse models compared with autoimmunediabetes-resistant strains [5,10]. A single transfer of DN Tregs could prevent the onset of type I diabetes in mice [5].…”