MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis
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eLife assessment
This study reports an important new resource, MHC class I and MHC class II reporter mice, which provide a means to monitor MHC activation in vivo. The authors use these mice to study inflammatory demyelination in two mouse models of multiple sclerosis. The study provides a compelling demonstration of the new reporter lines as a valuable tool for analysis of inflammation and neurodegeneration.
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Abstract
Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury, and disease.
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eLife assessment
This study reports an important new resource, MHC class I and MHC class II reporter mice, which provide a means to monitor MHC activation in vivo. The authors use these mice to study inflammatory demyelination in two mouse models of multiple sclerosis. The study provides a compelling demonstration of the new reporter lines as a valuable tool for analysis of inflammation and neurodegeneration.
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Reviewer #1 (Public Review):
In the article "MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis", Em P Harrington and colleagues describe two new mouse reporter models, that allow tracing cell lineages that activate the expression of CD74 and B2m genes, involved in MCHI and MHCII pathways, respectively. The authors then use these models to confirm the emergence of oligodendroglia with immune properties in the context of the EAE mouse model of MS. These mice models will be an excellent tool for the scientific community to investigate the contribution of MHCI and MHCII populations to the development of neuroimmunological disorders.
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Reviewer #2 (Public Review):
The manuscript from Harrington and colleagues describes the development and characterization of two new mouse resources that report MHC class I and class II expression. In these mice the tomato reporter gene was embedded into the gene encoding beta 2-microglobulin, to report class I expression, and separately in the CD74 gene, to report class II expression. The group highlights the need for such reporters by describing the growing interest in MHC expression by oligodendrocyte lineage cells in inflammatory CNS disorders, and they nicely demonstrate the utility of these reporters using mouse models of multiple sclerosis. There is also an emerging appreciation that immune cell infiltration into the CNS occurs in myriad neurological disorders, such that these models will likely have wide utility. The paper is …
Reviewer #2 (Public Review):
The manuscript from Harrington and colleagues describes the development and characterization of two new mouse resources that report MHC class I and class II expression. In these mice the tomato reporter gene was embedded into the gene encoding beta 2-microglobulin, to report class I expression, and separately in the CD74 gene, to report class II expression. The group highlights the need for such reporters by describing the growing interest in MHC expression by oligodendrocyte lineage cells in inflammatory CNS disorders, and they nicely demonstrate the utility of these reporters using mouse models of multiple sclerosis. There is also an emerging appreciation that immune cell infiltration into the CNS occurs in myriad neurological disorders, such that these models will likely have wide utility. The paper is clearly written and will be of wide interest.
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Reviewer #3 (Public Review):
In the human disease multiple sclerosis (MS) and in inflammatory demyelinating mouse models of MS, a subset of oligodendroglia express MHC genes. The role of MHC-expressing oligodendroglia in disease is unknown but thought to relate to a novel antigen-presenting function in these cells.
This study represents a fundamental advancement in approaches to detect and quantify the spatial and temporal expression of MHC I and MHC II genes in vivo through the generation of two reporter mice encoding CD74- or B2m-TdTomato fusion genes. This affords a highly quantitative method to isolate cells expressing the relevant fusion proteins and study their differential gene expression. The study advances the recent concept of oligodendroglia heterogeneity and in particular the presence of MHC expressing immune oligodendroglia.
Reviewer #3 (Public Review):
In the human disease multiple sclerosis (MS) and in inflammatory demyelinating mouse models of MS, a subset of oligodendroglia express MHC genes. The role of MHC-expressing oligodendroglia in disease is unknown but thought to relate to a novel antigen-presenting function in these cells.
This study represents a fundamental advancement in approaches to detect and quantify the spatial and temporal expression of MHC I and MHC II genes in vivo through the generation of two reporter mice encoding CD74- or B2m-TdTomato fusion genes. This affords a highly quantitative method to isolate cells expressing the relevant fusion proteins and study their differential gene expression. The study advances the recent concept of oligodendroglia heterogeneity and in particular the presence of MHC expressing immune oligodendroglia.
Prior work has shown oligodendrocyte heterogeneity, induction of MHC I and/or MHC II genes in "stressed" oligodendrocytes, and immunologic OPCs in MS at the transcriptional level (Schirmer 2019, Jakel 2019, Absinta 2021). Authors of the current work have shown that OPC differentiation is impaired by effector T cells, that IFNγ induces the MHC class I in these cells and that class I expressing OPC can present antigen, in vitro, to CD8 T cells (Harrington 2020, Kirby 2019). However, a deeper understanding of 1) how common is this process under different pathologic conditions, 2) where and when does MHC I and MHC II expression in oligodendroglia occur during a multistep pathophysiologic process, and 3) what is the full transcriptional characterization of immune oligodendroglia and how do they differ from other oligodendroglia, is lacking. The work presented in this manuscript address this gap and provides a tool for investigation into these questions for the community.
The investigators created two reporter mice - a CD74-TdTomato (class II) and a B2m-TdTomato (class I) strain. Figure 1 shows the targeting strategy, genotypes, and transgene expression in CD45, CD19, and CD3 cells from blood and secondary lymphoid tissue, demonstrating anticipated expression. Fig 1F and G show expression of CD74-TdT and B2m-TdT, respectively, in transverse histologic sections through the spinal cord of EAE mice with clinical scores of 0, 1.5, and 3.0 (baseline expression in naïve mice is shown in Fig 1 supp 3 and 4). Finally, supplement 5 shows higher power images, and quantitation of TdT as a function of other immunologic markers. The data nicely shows the fidelity of expression in relevant cell types and induction in vivo in EAE. In addition, the data shows that the transgene does not obviously impact expression quantitatively (Fig 1 sup 2).
The data in Figure 2 are central to the overall concept. The authors nicely demonstrate the induction of CD74-TdT and B2m-TdT in interferon gamma-treated oligodendrocytes as well as other cell types. Oligodendrocytes identified by olig2 are present in the spinal cord of mice with EAE and their frequency increases as the EAE severity increases. A strong correlation is seen between the severity of EAE and the percent of olig2 cells expressing the class I or class II gene.
In figure 3, scRNA seq performed on cells isolated from CD74-TdT or B2m-TdT mice with EAE reveals multiple subclusters of oligodendrocytes, one of which is high in MHC l as well as in other genes involved with antigen processing. The experiments are carefully conducted and contaminating cell populations were eliminated from the analysis.
An outstanding accomplishment, providing a resource to study multiple aspects of MHC I and MHC II cell-specific expression, transcriptional profiles in relevant cell types, and temporal course of activation. Most importantly, this resource will allow for a deeper quantitative analysis of the immune oligodendroglia phenotype and explore potential function in disease models.
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