Role of inhibitory signaling in peripheral B cell tolerance

Abstract

At least 20% of B cells in the periphery expresses an antigen receptor with a degree of self-reactivity. If activated, these autoreactive B cells pose a risk as they can contribute to the development of autoimmune diseases. To prevent their activation, both B cell-intrinsic and extrinsic tolerance mechanisms are in place in healthy individuals. In this review article, I will focus on B cell-intrinsic mechanisms that prevent the activation of autoreactive B cells in the periphery. I will discuss how inhibitory signaling circuits are established in autoreactive B cells, focusing on the Lyn-SHIP-1-SHP-1 axis, how they contribute to peripheral immune tolerance, and how disruptions of these circuits can contribute to the development of autoimmunity.

Keywords: B cells; autoimmunity; protein kinases/phosphatases; signal transduction; tolerance/suppression/anergy.

Figure 1.. Regulation of BCR signaling.

I) Upon BCR crosslinking Lyn phosphorylates the ITAMs of CD79A/CD79B resulting in the recruitment and activation of Syk. II) Lyn and Syk activate PI3K which phosphorylates PI(4,5)P2 to generate PI(3,4,5)P3. III) A signaling cascade activates multiple pathways important for B cell activation. PI(3,4,5)P3 plays an important role in facilitating activating signaling via the recruitment of key proteins that contain PH domains. IV) ITIM/ITSM-containing receptors come in proximity to actively signaling BCRs. Lyn phosphorylates the ITIM/ITSM tyrosine leading to the recruitment and activation of SHP-1 and SHIP-1. V) The tyrosine phosphatase SHP-1 inhibits signaling by dephosphorylating key tyrosines. VI) The inositol phosphatase SHIP-1 inhibits PI3K-dependent signaling by dephosphorylating PI(3,4,5)P3 to PI(3,4)P2. PTEN also counteracts PI3K signaling by dephosphorylating PI(3,4,5)P3 to PI(4,5)P2.

Figure 2.. Initiation of inhibitory signaling in autoreactive B cells.

I) Self-antigens that contain a ligand for an inhibitory receptor can directly recruit this inhibitory receptor to the BCR. II) Ligands for an inhibitory receptor can be part of the BCR (e.g. glycans) or recruited to the BCR, resulting in recruitment of the inhibitory receptor to the BCR. III) The BCR may act as an inhibitory receptor via ITAMi signaling.