MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis

eLife, 2023 · DOI: https://doi.org/10.7554/eLife.82938 · Published: April 14, 2023

Simple Explanation

Nerve cells in the brain and spinal cord are surrounded by a layer of insulation called myelin that allows cells to transmit messages to each other more quickly and efficiently. This protective sheath is produced by cells called oligodendrocytes which together with their immature counterparts can also repair damage caused to myelin. Recently it was discovered that mature and immature oligodendrocytes (which are collectively known as oligodendroglia) sometimes express proteins normally restricted to the immune system called major histocompatibility complexes (or MHCs for short). Researchers believe that MHC expression may allow oligodendroglia to interact with immune cells, potentially leading to the removal of oligodendroglia by the immune system as well as inflammation that exacerbates damage to nerves and hinders myelin repair. To address this, Harrington, Catenacci et al. created a genetically engineered mouse model in which the MHC-expressing oligodendroglia also generated a red fluorescent protein that could be detected under a microscope. This revealed that only a small number of oligodendroglia in the nervous system had MHCs, but these cells were located in areas of the brain and spinal cord with the highest inflammatory activity.

Study Duration

Not specified

Participants

Mice (B2mtdT and Cd74tdT reporter lines, wild-type C57BL/6, 2D2, OT-II)

Evidence Level

Not specified

Key Findings

1
MHC class I and II reporter mice enable reliable detection of immune oligodendroglia in the CNS.
2
The number of tdT+Olig2+ oligodendroglia was significantly higher in clinically symptomatic compared to pre-symptomatic score 0 animals in both B2mtdT and Cd74tdT spinal cord
3
MHC reporter expression was found in some Sox9+ astrocytes in EAE lesions of both B2mtdT and Cd74tdT animals, suggesting that astrocytes also upregulate MHC in the context of inflammation.

Research Summary

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. To enable detection of which cells upregulate MHC pathways in vivo, we generated two novel MHC I and MHC II reporter mouse lines that express tdTomato when these pathways are activated, and used these lines to define their incidence and transcriptional characteristics in two mouse models of inflammatory demyelination. Our studies reveal that MHC class I and II reporter mice enable reliable detection of immune oligodendroglia in the CNS. Quantitative analysis from naïve and inflammatory disease model mice reveals that these glial cells represent a small, but diverse population that increase in the inflammatory environment

Practical Implications

Understanding Disease Progression

The frequency of immune oligodendroglia correlated with disease severity, suggesting a relationship with behavioral presentation that could be used to track the progression and treatment of demyelinating disease.

Targeted Therapies

Identifying the phenotypic changes exhibited by cells with activated MHC pathways will help define the phenotypic changes they exhibit in diverse disease and injury contexts, and provide new insight into the complex cellular interactions that modify disease progression and repair.

Broader Applications

These reporter mice will facilitate analysis of neuronal MHC signaling in other injury and disease contexts, expanding our knowledge about the prevalence and impact of MHC signaling in the CNS.

Study Limitations

1
Full-length sequencing of insert was unsuccessful due to redundancy in tdTomato sequence.
2
The reporter lines may not fully represent the complexity of MHC regulation in all cell types or disease contexts.
3
There were very few astrocytes and neurons sequenced, likely due to difficulty in isolating these populations with papain dissociation

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