Скачать с ютуб Michael Cancro: B cell selection and survival: First order considerations for immunogenicity в хорошем качестве

Michael Cancro: B cell selection and survival: First order considerations for immunogenicity

Competition for limited, cell extrinsic survival factors is a general feature of the peripheral selection checkpoints involved in B lymphocyte maturation, activation and memory. Perhaps the best-characterized example involves BLyS family cytokines and receptors, which governs survival and differentiation within B cell subsets. Discovery of the BLyS cytokine and receptor family has proven a watershed event, significantly advancing our understanding of B lymphocyte selection and homeostasis. This family includes two ligands, BLyS (also termed BAFF) and APRIL; as well as three receptors, BR3 (also termed BAFFr), TACI, and BCMA. Members of this molecular family play critical roles in maintaining immunological tolerance, by impacting selection and survival in nearly all B cell subsets. Cells in the transitional and mature, pre-immune B lineage subsets rely on BLyS signals via the BR3 receptor for survival. In contrast to tolerogenic elimination at the BM immature B cell stage, the transitional checkpoint displays plasticity by integrating BCR-mediated selection with BLyS-mediated peripheral B cell homeostasis. Thus, when BLyS levels are elevated, transitional selection is “relaxed,” so that B cells that would normally be negatively selected instead survive to join mature naïve pools. Mounting, evidence suggests analogous competitive checkpoints for both germinal center B cells and plasma cells. In contrast to pre-immune pools, B cells in recently activated and antigen-experienced subsets shift their BLyS receptor profiles and hence their ligand reliance. For example, short-lived antibody-forming cells adopt a TACI dominated BLyS receptor signature, whereas germinal center (GC) B cells profoundly down-regulate TACI but retain BR3. The lack of TACI on GC B cells leads to a paucity of retained BLyS in the GC, such that the sole local source of BLyS in the GC is the TFH cell. Moreover, BLyS expression by GC TFH is crucial for appropriate GC evolution, since efficient affinity maturation fails if T cells are BLyS deficient. Finally, long-lived plasma cell pools express BCMA, shifting reliance to APRIL. Considered together, these observations suggest that deliberately altering BLyS levels might be a means for manipulating B cell repertoire selection in order to (1) restore self-tolerance in autoimmunity, (2) remodel the repertoire to accommodate neo-self antigens introduced through biologicals, transplantation and gene therapy, or (3) temporarily expand B cell repertoire diversity to reveal novel, therapeutically useful specificities.