The Spontaneous Autoimmune Neuromyopathy in ICOSL−/− NOD Mice Is CD4+ T-Cell and Interferon-γ Dependent

Abstract

Abrogation of ICOS/ICOS ligand (ICOSL) costimulation prevents the onset of diabetes in the non-obese diabetic (NOD) mouse but, remarkably, yields to the development of a spontaneous autoimmune neuromyopathy. At the pathological level, ICOSL−/− NOD mice show stronger protection from insulitis than their ICOS−/− counterparts. Also, the ICOSL−/− NOD model carries a limited C57BL/6 region containing the Icosl nul mutation, but, in contrast to ICOS−/− NOD mice, no gene variant previously reported as associated to NOD diabetes. Therefore, we aimed at providing a detailed characterization of the ICOSL−/− NOD model. The phenotype observed in ICOSL−/− NOD mice is globally similar to that observed in ICOS−/− and ICOS−/−ICOSL−/− double-knockout NOD mice, manifested by a progressive locomotor disability first affecting the front paws as observed by catwalk analysis and a decrease in grip test performance. The pathology remains limited to peripheral nerve and striated muscle. The muscle disease is characterized by myofiber necrosis/regeneration and an inflammatory infiltrate composed of CD4+ T-cells, CD8+ T-cells, and myeloid cells, resembling human myositis. Autoimmune neuromyopathy can be transferred to NOD.scid recipients by CD4+ but not by CD8+ T-cells isolated from 40-week-old female ICOSL−/− NOD mice. The predominant role of CD4+ T-cells is further demonstrated by the observation that neuromyopathy does not develop in CIITA−/−ICOSL−/− NOD in contrast to β2microglobulin−/−ICOSL−/− NOD mice. Also, the cytokine profile of CD4+ T-cells infiltrating muscle and nerve of ICOSL−/− NOD mice is biased toward a Th1 pattern. Finally, adoptive transfer experiments show that diabetes development requires expression of ICOSL, in contrast to neuromyopathy. Altogether, the deviation of autoimmunity from the pancreas to skeletal muscles in the absence of ICOS/ICOSL signaling in NOD mice is strictly dependent on CD4+ T-cells, leads to myofiber necrosis and regeneration. It provides the first mouse model of spontaneous autoimmune myopathy akin to human myositis.

Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation

“…These studies did not differentiate between the role of ICOS in effector versus Treg cells, and it is possible that ICOS plays a specific role in Treg cellmediated immune regulation in the CNS. Indeed, in NOD mice, ICOS deficiency protects against the spontaneous development of autoimmune type 1 diabetes but results in the development of neuromuscular autoimmunity associated with inflammatory cell infiltrates in the CNS (54,55). This condition resembles the spontaneous hind limb paresis associated with sciatic nerve demyelination and inflammation we observed in FYC-p110a fl d fl mice (aged 32-81 wk).…”

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

“…Possibly due to the dual role of ICOS in promoting Teff and Treg cells, conflicting results have been reported in nonobese diabetes (NOD) mice, a murine model of type 1 diabetes (T1D). ICOS and ICOSL knockout drastically reduced diabetes incidence . This correlated well with slower and milder inflammation in pancreatic β islets, indicating the crucial role of ICOS signaling in the activation of autoreactive pathogenic T cells.…”

“…This correlated well with slower and milder inflammation in pancreatic β islets, indicating the crucial role of ICOS signaling in the activation of autoreactive pathogenic T cells. However, most T1D‐free ICOS‐ and ICOSL‐deficient NOD mice developed hind leg paralysis due to a shift of autoimmune targets from β islet to neuromuscular tissues . Although it was proposed that the impact of ICOSL deficiency has been imprinted in the early activation stage of autoreactive T cells, further research should be done to investigate whether ICOS signaling promotes selection of thymic Treg cells specific to tissue‐restricted antigens to protect against autoimmune attack.…”

Icos gene disruption in non‐obese diabetic mice elicits myositis associated with anti‐troponin T3 autoantibodies

“…Interestingly, these mice spontaneously displayed a muscle deficiency compatible with a myositis [11]. In the Icosl −/− NOD model, further studies have shown that the muscle pathology is linked to muscle‐infiltrating CD4 + T cells producing IFNγ [12]. Features of myositis have been found in Icos −/− NOD mice, but the disease has not been characterised.…”