Different Nuclear Signals are Activated by the B Cell Receptor during Positive Versus Negative Signaling

Immunity 1997, 6: 419-428

By James I. Healy, Ricardo E. Doimetsch, Luika A. Timmerman, Jason G. Cyster, Mathew L. Thomas, Gerald R. Crabtree, Richard S. Lewis, and Christopher C. Goodnow

B cells display antibodies on their cell membranes to serve as antigen receptors. The binding of antigen to these membrane bound antibodies leads to cross-linking induces what are thought to be positive signals to the cell nucleus to trigger the process of antibody production, cell proliferation and differentiation. The binding of self antigen, by contrast, induces negative signaling which actively promotes self-tolerance, by inhibiting B cell survival, maturation, proliferation, migration, and antibody secretion.

This publication explores the signaling systems employed by naive B cells that respond to foreign antigen and by self-tolerant B cells. These studies involve a transgenic mouse system making high levels of B cells to hen egg lysozyme (HEL) as a foreign antigen. If the B cells mature in the mouse without being exposed to HEL (do not see HEL as self), then they will respond positively to HEL as a foreign upon exposure. If, on the other hand, these same transgenic mice have been engineered to also continually express HEL, the same B cells see HEL as self, become anergic, and respond to antigen in a negative manner.

The B cell initiates its positive signaling response by initiating a biochemical cascade of tyrosine kinases and second messengers such as calcium fluxes. These signals bring transcription factors such as NF-AT and NF-kB into the nucleus and activate protein kinases such as ERK and JNK. These transcription factors activate processes that eventually lead to growth, differentiation and antibody production.

For naive B cells, HEL is seen as a foreign antigen. Its presence triggers large calcium fluxes and activates signals into the nucleus through NF-AT, NF-kB, JNK and ERK. By contrast, in self-tolerant B cells, HEL is seen as self, triggers low calcium fluxes, and activates NF-AT and ERK, but not NF-kB or JNK.

The authors conclude that these signaling differences are due to differences in tyrosine kinase activity and calcium signaling. Previous studies have shown that self-tolerant B cells have lower activities of tyrosine kinase when the B cell antigen receptor is cross-linked. This lowered kinase activity would lead to lower calcium fluxes. The lower calcium levels would result in differential activation of NF-AT over NF-kB and ERK over JNK. The observation that NF-AT and ERK are active in self-tolerant B cells suggests a possible role for these two activators, in the absence of NF-kB and JNK, in negative signaling.