HSP90alpha and HSP90beta isoforms selectively modulate MHC class II antigen presentation in B cells

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Heat shock protein (HSP) 90 has two isoforms, alpha and beta, primarily found in the cytoplasm.
• HSP90alpha is known to chaperone for MHC class I presentation, but its role in MHC class II presentation is less understood.
• The specific involvement of HSP90 isoforms in presenting autoantigens like GAD via MHC class II is unclear.

Purpose of the Study:

• To investigate the role of HSP90alpha and HSP90beta isoforms in regulating MHC class II presentation of the diabetes autoantigen glutamic acid decarboxylase (GAD).
• To determine if HSP90 isoforms selectively regulate antigen presentation or broadly affect MHC class II pathways.

Main Methods:

• Utilized human B lymphoblasts and antigen-presenting cells (APCs).
• Inactivated HSP90 function using geldanamycin and radicicol.
• Employed small interfering RNA (siRNA) for gene knockdown of HSP90alpha and HSP90beta.
• Assessed MHC class II expression and presentation of various antigens, including GAD.
• Investigated HSP90 association with antigens ex vivo and in cells.

Main Results:

• Inactivation of HSP90 inhibited MHC class II presentation of both exogenous and endogenous GAD, but not other antigens.
• HSP90 inhibition induced a stress response in APCs, yet cell stress alone did not affect GAD presentation.
• Knockdown of HSP90alpha or HSP90beta specifically impaired MHC class II presentation of GAD.
• HSP90 was found to associate with GAD.
• Precomplexing HSP90 with GAD enhanced exogenous GAD presentation.

Conclusions:

• HSP90alpha and HSP90beta are essential for the selective regulation of MHC class II presentation of the GAD autoantigen.
• HSP90 plays a specific role in GAD antigen processing and presentation, independent of general stress responses or MHC class II expression levels.
• These findings highlight a novel function for HSP90 isoforms in adaptive immunity, particularly in autoimmune disease contexts.