Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy

Abstract

B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors. Conversely, in anergic B cells, chronic antigen stimulation drives biased monophosphorylation of CD79 ITAMs leading to recruitment of Lyn, but not Syk, which docks only to bi-phosphorylated ITAMS. In this context, Lyn appears to function primarily as a driver of inhibitory signaling pathways promoting the inhibition of the PI3K pathway by inositol phosphatases, SHIP-1 and PTEN, which hydrolyze PIP3 to PIP2. Lyn may also exert negative regulation of signaling through recruitment of SHP-1, a tyrosine phosphatase that dephosphorylates activating signaling molecules. Alleles of genes that encode or regulate expression of components of this axis, including SHIP-1, SHP-1, Csk/PTPn22, and Lyn, have been shown to confer risk of autoimmunity. This review will discuss functional interplay of components of this pathway and the impact of risk alleles on its function.

Keywords: B cells; Pten; SHIP-1; SHP-1; anergy; kinases; lyn; phosphatases.

Figure 1

Antigen receptor signaling in naïve and anergic B cells. B cell antigen receptor (BCR) aggregation in naïve cells leads proximally to phosphorylation of CD79a and CD79b immunoreceptor tyrosine-based activation motif (ITAM) tyrosines. This phosphorylation allows recruitment of the Src-family kinase Lyn to the receptor where it binds through its SH2 domain and its activity is derepressed. Lyn mediates activation of the phosphoinositide 3-kinase (PI3-kinase) pathway via phosphorylation of CD19, and the PI(3,4,5)P3 product of this pathway sequesters BLNK, PLCγ, and BTK for function in signaling. Phosphorylation of both ITAM tyrosines leads to binding of SYK via its dual SH2 domains and to subsequent activation. Under conditions of chronic antigen stimulation (anergy), the ITAMs on CD79a are preferentially monophosphorylated, recruiting Lyn to the complex. Lyn, in its negative regulatory role, recruits the function of the inositol phosphatases, SHIP-1 and PTEN, as well as the tyrosine phosphatase, SHP-1. These regulatory phosphatases will then exert their inhibitory function on downstream effector molecules, abrogating stimulatory BCR signaling. Bias toward stimulation of inhibitory circuitry is reversed upon removal of the antigen receptor stimulus.