Targeting Mcl-1 to Restore IL-10-Driven Breg Suppression Reverses Allergic Asthma

Regulatory B cells (Bregs) suppress allergic inflammation primarily through interleukin-10 (IL-10), yet the intrinsic mechanisms constraining their regulatory capacity remain incompletely understood. Although the anti-apoptotic protein Mcl-1 is essential for B cell survival, its potential non-canonical roles in Breg-mediated immune regulation are unknown.

B cell-specific Mcl1^ΔCD19mice and OVA-induced airway allergy models were used to assess Breg function. Translational studies employed lentiviral MCL1overexpression in primary human B cells, PBMC-reconstituted NSG mice, and clinical B cell profiling from asthma patients. Rigorous experimental controls were implemented to exclude confounding effects from B cell developmental defects and compensatory anti-apoptotic signaling.

Compared with littermate controls, Mcl1^ΔCD19mice exhibited significantly attenuated airway hyperresponsiveness, pulmonary eosinophilia, and antigen-specific IgE levels (all p< 0.01), accompanied by a 4.2-fold increase in the absolute number of IL-10⁺Bregs (p< 0.001). B cells isolated from Mcl1^ΔCD19mice potently suppressed Th2 cytokine production and promoted type 1 regulatory T (Tr1) cell differentiation in an IL-10R-dependent manner. Mechanistically, Mcl-1 associates with the Il10promoter; this chromatin binding coincides with enrichment of the repressive histone mark H3K27me3 and reduced recruitment of RNA polymerase II. In humanized mice, enforced MCL1 overexpression in human B cells reduced IL-10 secretion by 65% and exacerbated airway inflammation. Furthermore, B cells from asthma patients displayed elevated endogenous MCL1 expression and correspondingly diminished IL-10 production. It should be noted that our human-subject analysis is limited by modest sample size, and further validation in larger patient cohorts is required.

Mcl-1 functions as an epigenetic suppressor of Il10transcription in B cells, independently of its canonical pro-survival role, thereby restraining Breg-mediated immune tolerance and promoting allergic airway inflammation. The B-cell Mcl-1/IL-10 axisrepresents a promising preclinical pathway for further investigation as a potential therapeutic target for allergic asthma, though pharmacological validation is still needed.