Regulation of self-tolerance and adaptive immunity by cell death and other cues

Division Of Basic Sciences - Nci

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Abstract

B lymphocytes assemble their antigen receptor genes (B cell receptor, BCR) during development in the bone marrow. Immature B cells with newly formed BCRs then mature further in the bone marrow and spleen, generating a diverse repertoire. Upon antigenic challenge, only B cells with the most suitable BCRs become activated, proliferate, and may initiate a germinal center (GC) reaction. In GCs, B cells introduce mutations into their BCR genes and undergo selection for increased antigen-binding affinity. This process also generates memory B cells and high-affinity, antibody-producing plasma cells. B cell affinity maturation requires help from specialized T cells, which are themselves regulated by dendritic cells (DCs). Both BCR assembly in the bone marrow and BCR mutation in GCs can produce self-reactive B cells. How these potentially dangerous cells are controlled remains a longstanding question in immunology. Our lab investigates apoptosis as a mechanism for eliminating self-reactive B cells. We found that few immature B cells undergo apoptosis in the bone marrow, but many do so in the blood and spleen. However, when we cloned BCRs from viable and apoptotic B cells, we found little evidence for the selective deletion of autoreactive B cells; notably, 90% of dying immature B cells in the spleen were not autoreactive. This suggests that most splenic immature B cells die due to lack of survival signals, rather than self-reactivity. While apoptosis of self-reactive B cells appears rare, it may still play an important role in B cell tolerance-a question we are actively investigating. Apoptosis may also regulate mature B cells participating in GC responses following vaccination, infection, or cancer. In collaborative work, we have shown that regulated plasma cell proliferation is linked to affinity maturation: high-affinity precursor plasma cells receive more T cell help and proliferate more than their low-affinity counterparts, explaining how diverse precursors contribute to affinity-matured plasma cell pools. Additionally, we have implicated B cells in the therapeutic response to anti-VEGF therapy combined with CTLA-4 and PD-L1 checkpoint blockade in cholangiocarcinoma, identifying B cell activation factor (BAFF) (a key regulator of B cell apoptosis and tolerance) as a critical factor elevated by this combination therapy.