Innate immune cell-derived BAFF induces non-canonical NF-κB activation to promote inflammatory response of ICOSL

Summary

This mechanistic study identifies an ICOSL-expressing B cell subset linked to T1D progression in patient cohorts and mouse models, and shows that innate immune cell–derived BAFF activates non-canonical NF-κB signaling to promote inflammatory responses. Findings reframe T1D pathogenesis to include a BAFF–ICOSL–B cell axis as a potential driver and therapeutic target.

Key Findings

• Identified an ICOSL-expressing B cell subset associated with T1D progression in human cohorts and mouse models.
• Innate immune cell–derived BAFF triggers non-canonical NF-κB activation, promoting inflammatory responses in ICOSL+ B cells.
• Functional analyses support a BAFF–ICOSL–B cell inflammatory pathway relevant to T1D pathogenesis.

Clinical Implications

While not directly practice-changing yet, the BAFF–ICOSL axis could inform biomarker development and guide future trials of BAFF/ICOSL-targeted therapies in T1D.

Limitations

• Sample sizes and effect estimates are not specified in the abstract, limiting appraisal of statistical robustness.
• Clinical translation is untested; no interventional validation of targeting the BAFF–ICOSL axis.

Future Directions

Validate ICOSL+ B cells as biomarkers in prospective T1D cohorts and test BAFF/ICOSL-targeted interventions in preclinical models followed by early-phase clinical trials.