RORα negatively regulates BCG-induced trained immunity

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Trained immunity involves lasting innate immune cell changes, enhancing responses to secondary challenges.
• Epigenetic, transcriptional, and metabolic reprogramming are key mechanisms in trained immunity development.

Purpose of the Study:

• To investigate the impact of gene variants on trained immunity after Bacillus Calmette-Guérin (BCG) vaccination.
• To identify genetic associations with BCG-induced trained immunity in human peripheral blood mononuclear cells (PBMCs).

Main Methods:

• Analysis of gene variants, specifically polymorphisms in the RORA gene, in relation to BCG-induced trained immunity.
• Measurement of cytokine production, cell morphology, reactive oxygen species (ROS), and lactate production in human PBMCs.
• Pharmacological inhibition of RORα and blocking of lactate dehydrogenase A (LDHA) and glycolysis.

Main Results:

• A strong association was found between RORA gene polymorphisms and BCG-induced trained immunity.
• Circulating natural RORα agonists negatively correlated with trained immunity strength.
• Pharmacological RORα inhibition in PBMCs boosted BCG-induced trained immunity, increasing cytokine production and altering cell characteristics.
• Blocking LDHA and glycolysis reduced cytokine production in BCG-trained cells treated with a RORα agonist.

Conclusions:

• RORα plays a significant role in trained immunity.
• RORα activity impacts human vaccination responses and potentially disease outcomes.
• Further investigation into RORα's role in trained immunity is warranted.