Vos Q, Lees A, Wu Z Q, Snapper C M, Mond J J
Department of Medicine, Uniformed Services, University of the Health Sciences, Bethesda, Maryland, USA.
Immunol Rev. 2000 Aug;176:154-70. doi: 10.1034/j.1600-065x.2000.00607.x.
Antigens that are expressed on the surface of pathogens in an organized, highly repetitive form can activate specific B cells by cross-linking of antigen receptors in a multivalent fashion. B cells respond to these multivalent antigens in the absence of MHC class II-restricted T-cell help by a mechanism that depends on the expression of a functional Bruton's tyrosine kinase (Btk). Accordingly, this class of immunogens has been designated T-cell-independent type 2 (TI-2) antigens. The unique properties of the B-cell response to TI-2 antigens are critically dependent on the formation of a small number of antigen receptor clusters, each of which contains approximately 10 to 20 antigen-bound membrane Ig (mIg) molecules. These clusters induce local membrane association of multiple activated Btk molecules, which results in long-term mobilization of intracellular ionized calcium. Such persistent calcium fluxes efficiently recruit transcription factors and thereby induce T-cell-independent B-cell activation and proliferation. While this first signal of multivalent mIg cross-linking can induce B-cell proliferation, we 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, but not by bivalent, antigen receptor 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 recognition 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 the B cell and the innate immune system, and facilitates the mIg signal transduction by recruitment of CD21 in the immune response. Thus, the TI-2 response provides the host with a combination of "the best of both worlds": the recruitment of the fine specificity of the adaptive immune response and the utilization of both the speed of the innate immune system and the wealth of cytokines produced by its member cells upon stimulation by pathogenic organisms or their products. By combining these two pathways, the TI-2 response enables the host to rapidly produce antigen-specific Ig effector molecules that can be secreted at a sufficient rate to keep up with the rapid multiplication of invading infectious microorganisms, and will also prevent the intracellular spreading of a significant part of this population.
以有组织、高度重复的形式在病原体表面表达的抗原，能够通过以多价方式交联抗原受体来激活特定的B细胞。在没有MHC II类限制性T细胞辅助的情况下，B细胞通过一种依赖功能性布鲁顿酪氨酸激酶（Btk）表达的机制对这些多价抗原作出反应。因此，这类免疫原被指定为2型非T细胞依赖性（TI-2）抗原。B细胞对TI-2抗原反应的独特特性关键取决于少量抗原受体簇的形成，每个簇包含大约10到20个与抗原结合的膜免疫球蛋白（mIg）分子。这些簇诱导多个活化的Btk分子在局部与膜结合，从而导致细胞内游离钙的长期动员。这种持续的钙流有效地募集转录因子，进而诱导非T细胞依赖性B细胞的活化和增殖。虽然多价mIg交联的这第一个信号可以诱导B细胞增殖，但我们提出TI-2 Ig分泌反应需要第二个信号。我们发现，Toll样受体（TLR）家族成员的结合可以提供第二个信号，该信号选择性地诱导在被多价而非二价抗原受体结合激活的B细胞中分泌Ig。这一发现证明了一种普遍机制，通过该机制TLR识别病原体表面的分子基序，并为TI-2活化的B细胞提供第二个信号。此外，先天免疫系统细胞对这些非自身基序的TLR依赖性识别可以诱导这些细胞在TI-2反应中提供替代和/或额外的第二个信号。补体系统在B细胞和先天免疫系统之间提供了另一个联系，并通过在免疫反应中募集CD21促进mIg信号转导。因此，TI-2反应为宿主提供了“两全其美”的组合：募集适应性免疫反应的精细特异性，并利用先天免疫系统的速度及其成员细胞在受到致病生物或其产物刺激时产生的丰富细胞因子。通过结合这两条途径，TI-2反应使宿主能够快速产生抗原特异性Ig效应分子，这些分子能够以足够的速率分泌，以跟上入侵感染微生物的快速增殖，并且还将防止这一群体中很大一部分在细胞内扩散。
