B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms

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.