often called B-cell mitogens, a mitogen being a substance that induces cells to undergo mitosis. For example, LPS and bacterial DNA are both TI-1 antigens because they activate TLRs expressed by B cells (see Section 3-5) and can act as a mitogen. Naive murine B cells express most TLRs constitutively, but naive human B cells do not express high levels of most TLRs until they receive stimulation through the B-cell receptor. So by the time a B cell has been stimulated by antigen through its B-cell receptor, it is likely to express several TLRs and be responsive to stimulation by TLR ligands that accompany the antigens. Thus, when B cells are exposed to concentrations of TI-1 antigens that are 103–105 times lower than those used for polyclonal activation, only those B cells whose B-cell receptors specifically bind the TI-1 antigen become activated. At these low concentrations, amounts of TI-1 antigen sufficient for B-cell activation can only be concentrated on the B-cell surface with the aid of this specific binding (see Fig. 10.24, bottom panels). B-cell responses to TI-1 antigens in the early stages of an infection may be important in defense against several extracellular pathogens, but they do not lead to affinity maturation or memory B cells, both of which require antigen-specific T-cell help.
The second class of thymus-independent antigens—TI-2 antigens—consists of molecules that have highly repetitive structures, such as bacterial capsular polysaccharides. These contain no intrinsic B-cell-stimulating activity. Whereas TI-1 antigens can activate both immature and mature B cells, TI-2 antigens can activate only mature B cells; immature B cells, as we saw in Section 8-6, are inactivated by encounter with repetitive epitopes. Infants and young children up to about 5 years of age do not make fully effective antibody responses against polysaccharide antigens, and this might be because most of their B cells are immature.
Responses to several TI-2 antigens are prominently made by marginal zone B cells, a subset of nonrecirculating B cells that line the border of the splenic white pulp, and by B-1 cells (see Section 8-9). Marginal zone B cells are rare at birth and accumulate with age; they might therefore be responsible for most physiological TI-2 responses, which increase in efficiency with age. TI-2 antigens probably act by simultaneously cross-linking a critical number of B-cell receptors on the surface of antigen-specific mature B cells (Fig. 10.25, left
Fig. 10.25 B-cell activation by TI-2 antigens requires, or is greatly enhanced by, cytokines. Multiple cross-linking of the B-cell receptor by TI-2 antigens can lead to IgM antibody production (left panels), but there is evidence that in addition cytokines greatly augment these responses, and also lead to isotype switching (right panels). It is not clear where such cytokines originate, but one possibility is that dendritic cells, which may be able to bind the antigen through innate immune-system receptors on their surface and so present it to the B cells, secrete a soluble TNF-family cytokine called BAFF, which can activate class switching by the B cell.