IMMUNOLOGY2025™ Conference Recordings-B cell tolerance

Video Transcription

Video Summary

The talk describes how B-cell tolerance is established in two checkpoints: first in the bone marrow, where autoreactive B cells are removed centrally, and second in the periphery, where newly emigrated B cells are further filtered before becoming mature naïve B cells. Using single-cell antibody cloning and analysis of healthy donors and patients, the speaker shows that many autoimmune diseases feature defective central tolerance, allowing autoreactive B cells to leave the bone marrow. In contrast, peripheral tolerance failures lead to accumulation of autoreactive clones in mature naïve B cells across many autoimmune conditions.<br /><br />The speaker then identifies different molecular pathways controlling these checkpoints. Central tolerance depends largely on proper B-cell receptor signaling, while peripheral tolerance is regulated by T cells, especially regulatory T cells (Tregs). Humanized mouse models showed that functional human Tregs suppress autoreactive B-cell accumulation in the periphery. Disrupting antigen presentation or depleting Tregs caused autoreactive B-cell buildup.<br /><br />The talk also shows that anti-CTLA-4 checkpoint blockade, but not anti-PD-1, disrupts peripheral B-cell tolerance in mice and in melanoma patients, explaining some autoimmune side effects of immunotherapy. Finally, in IPEX patients, transplantation of functional Tregs restored peripheral B-cell tolerance, suggesting Treg therapy could help treat autoimmunity.

Keywords

B-cell tolerance

central tolerance

peripheral tolerance

autoreactive B cells

regulatory T cells

CTLA-4 blockade

autoimmune disease