A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells

Area of Science:

• Immunology
• Genetics
• Neuroscience

Background:

• Genome-wide association studies reveal numerous autoimmune disease susceptibility loci linked to immune cell gene activity.
• Identifying and functionally characterizing causal variants for autoimmune diseases remains a significant challenge.
• Histone deacetylase 7 (HDAC7) is implicated in immune cell function and autoimmune disease risk.

Purpose of the Study:

• To investigate the immunomodulatory role of a protective HDAC7 variant (rs148755202, HDAC7.p.R166H) associated with multiple sclerosis (MS).
• To elucidate the functional impact of HDAC7 on regulatory T cells (Tregs) and their role in neuroinflammation.

Main Methods:

• Transcriptomic analyses to assess the effect of wild-type HDAC7 on Treg-associated genes.
• Treg-specific conditional hemizygous deletion of HDAC7 in a mouse model of experimental autoimmune encephalitis (EAE).
• In vitro functional assays of Tregs transduced with the protective HDAC7 R166H variant.
• Generation of a knock-in mouse model with an orthologous HDAC7 R150H substitution for in vivo assessment.
• Single-cell RNA sequencing of brain-infiltrating Tregs in the knock-in mouse model.

Main Results:

• Wild-type HDAC7 regulates genes critical for the function of Foxp3+ regulatory T cells (Tregs).
• Treg-specific deletion of HDAC7 exacerbated EAE severity, indicating its protective role.
• Tregs expressing the protective HDAC7 R166H variant demonstrated enhanced suppressive capacity in vitro.
• The HDAC7 R150H knock-in mouse model exhibited reduced EAE severity, linked to altered Treg transcriptomes in the brain.

Conclusions:

• The protective HDAC7 variant enhances Treg function, offering a potential therapeutic avenue for MS and other autoimmune diseases.
• Dysregulation of epigenetic modifiers like HDAC7 can influence autoimmune disease onset and progression.
• This study provides a framework for translating genetic findings into functional characterization using in vitro and in vivo models.