Q. Vos et al., B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms, IMMUNOL REV, 176, 2000, pp. 154-170
Antigens that are expressed on the surface of pathogens in an organized, hi
ghly repetitive form can activate specific B cells by cross-linking of anti
gen receptors in a multivalent fashion. B cells respond to these multivalen
t antigens in the absence of MHC class II-restricted T-cell help by a mecha
nism that depends on the expression of a functional Bruton's tyrosine kinas
e (Btk). Accordingly, this class of immunogens has been designated T-cell-i
ndependent type 2 (TI-2) antigens. The unique properties of the B-cell resp
onse to TI-2 antigens are critically dependent on the formation of a small
number of antigen receptor clusters, each Of which contains approximately 1
0 to 20 antigen-bound membrane Ig (mIg) molecules. These clusters induce lo
cal membrane association of multiple activated Btk molecules, which results
in long-term mobilization of intracellular ionized calcium. Such persisten
t calcium fluxes efficiently recruit transcription factors and thereby indu
ce T-cell-independent B-cell activation and proliferation. While this first
signal of multivalent mig cross-linking can induce B-cell proliferation, w
e propose that a second signal is required for a TI-2 Ig secretory response
. We have found that engagement of members of the Toll-like receptor (TLR)
family could provide second signals that selectively induce Ig secretion in
B cells that were activated by multivalent, bur not by bivalent, antigen r
eceptor engagement. This finding demonstrates a general mechanism by which
TLRs recognize molecular motifs on the surface of pathogens and provide the
TI-2-activated B cell with a second signal. In addition, TLR-dependent rec
ognition of these non-self motifs by cells of the innate immune system can
induce these cells to provide alternative and/or additional second signals
in the TI-2 response. The complement system provides another link between t
he B cell and the innate immune system, and facilitates the mig signal tran
sduction by recruitment of CD21 in the immune response. Thus, the TI-2 resp
onse provides the host with a combination of "the best of both worlds": the
recruitment of the fine specificity of the adaptive immune response and th
e utilization of both the speed of the innate immune system and the wealth
of cytokines produced by its member cells upon stimulation by pathogenic or
ganisms or their products. By combining these two pathways, the TI-2 respon
se enables the host to rapidly produce antigen-specific Ig effector molecul
es that can be secreted at a sufficient rate to keep up with the rapid mult
iplication of invading infectious microorganisms, and will also prevent the
intracellular spreading of a significant part of this population.