Age-dependent divergent effects of OX40L treatment on the development of diabetes in NOD mice

Abstract

Earlier, we have shown that GM-CSF derived bone marrow dendritic cells (G-BMDCs) can expand Foxp3+ regulatory T-cells (Tregs) through a TCR-independent, but IL-2 dependent mechanism that required OX40L/OX40 interaction. While some reports have shown suppression of autoimmunity upon treatment with an OX40 agonist, others have shown exacerbation of autoimmune disease instead. To better understand the basis for these differing outcomes, we compared the effects of OX40L treatment in 6-week-old pre-diabetic and 12-week-old near diabetic NOD mice. Upon treatment with OX40L, 6-week-old NOD mice remained normoglycemic and showed a significant increase in Tregs in their spleen and lymph nodes, while 12-week-old NOD mice very rapidly developed hyperglycemia and failed to show Treg increase in spleen or LN. Interestingly, OX40L treatment increased Tregs in the thymus of both age groups. However, it induced Foxp3+CD103+CD38− stable-phenotype Tregs in the thymus and reduced the frequency of autoreactive Teff cells in 6-week-old mice; while it induced Foxp3+CD103−CD38+ labile-phenotype Tregs in the thymus and increased autoreactive CD4+ T cells in the periphery of 12-week-old mice. This increase in autoreactive CD4+ T cells was likely due to either a poor suppressive function or conversion of labile Tregs into Teff cells. Using ex vivo cultures, we found that the reduction in Treg numbers in 12-week-old mice was likely due to IL-2 deficit, and their numbers could be increased upon addition of exogenous IL-2. The observed divergent effects of OX40L treatment were likely due to differences in the ability of 6- and 12-week-old NOD mice to produce IL-2.

Soluble OX40L and JAG1 Induce Selective Proliferation of Functional Regulatory T-Cells Independent of canonical TCR signaling

“…We and others have observed that treatment of 6-week old NOD mice with either OX40 L or an anti-OX40 agonistic antibody (OX86) can increase CD4 + CD25 + Foxp3 + Treg cells and protect NOD mice from developing diabetes4344. However, treating 12-week old NOD mice with OX40 L accelerated diabetes development likely due to an increased pro-inflammatory environment associated with aging in these mice44. Thus, the outcome of treatment with OX40 L alone appears to be age-dependent in NOD mice.…”

The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice

“…Ox40 agonist treatment exacerbated models of experimental uveitis (67,68) and promoted inflammatory lung pathology in B6 mice (69). However, in other models, the diseasepromoting effects of Ox40 agonism depended upon age and disease severity of the animals (e.g., in experimental autoimmune encephalitis and type 1 diabetes, in which treatment promoted disease during later or effector phases but protected from disease when provided during early or priming phases) (70)(71)(72). Evidence from those studies suggests that the disease-promoting versus disease-preventing effects of Ox40 agonism might be explained by how each treatment impacted Tregs in these models.…”

Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis

“…Abundant literature has reported that while CX3CL1 is significant for T cell migration, granulocyte-macrophage colony-stimulating factor (GM-CSF) is the key chemokine for survival, proliferation, differentiation, maturation and functional activation of hematopoietic cells, including macrophages and monocytes1819. GM-CSF receptor is a heterodimer composed of α and β subunits20. A reduction of macrophages in synovial tissue has been correlated with improvement in the disease activity score, thus antagonizing GM-CSF was found to markedly reduce established disease in mouse models of RA2122.…”