γ-Interferon-regulated chaperone governs human lymphocyte antigen class II expression

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Antigen presentation by human lymphocyte antigen (HLA) class II peptide receptors is crucial for immune surveillance against infections.
• Expression of HLA class II, HLA-DM, and invariant chain in antigen-presenting cells (APCs) is primarily regulated by the interferon gamma (IFNγ)-inducible class II transactivator (CIITA).

Purpose of the Study:

• To investigate the role of B-associated transcript 3 (BAT3) in the regulation of HLA class II antigen processing and presentation.
• To elucidate the mechanism by which IFNγ controls HLA class II expression through CIITA and its associated factors.

Main Methods:

• Analysis of BAT3 expression levels in response to IFNγ in various cell lines and primary macrophages.
• Investigating the interaction between BAT3 and CIITA using cellular localization studies (cytosol to nucleus translocation).
• Assessing the impact of BAT3 modulation (elevation and depletion) on HLA class II, HLA-DM, and invariant chain expression.

Main Results:

• Interferon gamma (IFNγ) significantly increases BAT3 transcription in multiple cell types, including tumor cell lines and macrophages.
• Elevation of BAT3 enhances, while depletion reduces, the expression of HLA class II, HLA-DM, and invariant chain.
• BAT3 functions as a chaperone for CIITA, and both proteins translocate to the nucleus upon IFNγ treatment, where CIITA activates HLA class II genes.

Conclusions:

• BAT3 is identified as a novel key regulator in the HLA class II processing pathway.
• A mechanism is proposed where parallel IFNγ-mediated regulation of CIITA and its chaperone BAT3 controls the expression of HLA class II pathway components, impacting immune system activation.