Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

Abstract

Summary We previously reported that infection of different mouse strains with a recombinant HSV-1 expressing IL-2 (HSV-IL-2) caused CNS demyelination. Histologic examination of infected IL-2rα −/− , IL-2rβ −/− , and IL-2rγ −/− mice showed demyelination in the CNS of IL-2rα −/− and IL-2rβ −/− mice but not in the CNS of IL-2rγ −/− -infected mice. No demyelination was detected in mice infected with control virus. IL-2rγ −/− mice that lack type 2 innate lymphoid cells (ILC2s) and ILCs, play important roles in host defense and inflammation. We next infected ILC1 −/− , ILC2 −/− , and ILC3 −/− mice with HSV-IL-2 or wild-type (WT) HSV-1. In contrast to ILC1 −/− and ILC3 −/− mice, no demyelination was detected in the CNS of ILC2 −/− -sinfected mice. However, transfer of ILC2s from WT mice to ILC2 −/− mice restored demyelination in infected recipient mice. CNS demyelination correlated with downregulation of CCL5 and CXCL10. This study demonstrates that ILC2s contribute to HSV-IL-2-induced CNS demyelination in a mouse model of multiple sclerosis.

Protocol for a mouse CNS demyelination model induced by a combination of HSV-1 and IL-2

“…To dissect the molecular and cellular mechanisms of demyelination induced by HSV1-IL-2, we infected HSV-IL-2 to various genetically engineered mice, or mice with adoptively transferred cells. We found that both type 2 innate lymphocytes (ILC2s) and T cells play a role in induction of demyelination, because mice lacking these cells did not develop demyelination following infection with HSV1-IL-2, whereas transfer of ILC2s isolated from wild-type mice into recipient ILC2-deficient mice ( Hirose et al., 2020 ) or T cells isolated from wild-type mice into SCID mice ( Zandian et al., 2011a ) infected with HSV1-IL-2 restored the demyelination phenotype. In this section, we describe the method for intravenous injection of immune cells to test their function in this mouse model.…”

“…Female mice aged 7–9 weeks were used. Isolate ILC2 cells as described previously ( Hirose et al., 2020 ; Moro et al., 2015 ) and transfer into a 1.5 mL tube. Centrifuge at 500 × g for 10 min, 4°C.…”

“…Isolate ILC2 cells as described previously ( Hirose et al., 2020 ; Moro et al., 2015 ) and transfer into a 1.5 mL tube.…”

“…Here, we describe a mouse model to induce and evaluate demyelinating disease with both a viral and an immune component via ocular infection with a recombinant herpes simplex virus expressing murine interleukin-2. For complete details on the use and execution of this protocol, please refer to Hirose et al. (2020) .…”

“…For complete details on the use and execution of this protocol, please refer to Hirose et al. (2020) .…”