* In humoral immune responses, B lymphocytes are activated by antigen and secrete antibodies that act to eliminate the antigen. Both protein and nonprotein antigens can stimulate antibody responses. B cell responses to protein antigens require the contribution of CD4+ helper T cells specific for the antigen.
* Helper T cell-dependent B cell responses to protein antigens require initial activation of naive T cells y y y in the T cell zones and of B cells in lymphoid follicles in lymphoid organs. The activated lymphocytes migrate toward one another and interact at the edges of follicles, where the B cells present the antigen to helper T cells.
Activated helper T cells express CD40L, which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates initial B cell proliferation and differentiation.
Stimulation of activated B cells at extrafollicular sites by helper T cells leads to the formation of extrafollicular foci where some isotype switching occurs and short-lived plasma cells are generated. Some activated helper T cells differentiate into specialized TFH cells that express high levels of ICOS and CXCR5 and secrete IL-21. TFH cells and activated B cells migrate into the follicle, and TFH cells activate these specific B cells to initiate the formation of germinal centers. The late events in T cell-dependent antibody responses, including extensive isotype switching, somatic mutation, affinity maturation, generation of memory B cells, and induction of long-lived plasma cells, take place within germinal centers.
* Helper T cell-derived signals, including CD40L and cytokines, induce isotype switching in B cells by a process of switch recombination, leading to the production of various Ig isotypes. Isotype switching requires the induction of AID, a cytidine deam-inase that converts cytosine to uracil in single-stranded DNA, and different cytokines allow AID to access distinct downstream heavy chain loci.
* Affinity maturation occurs in germinal centers and leads to increased affinity of antibodies during the course of a T cell-dependent humoral response. Affinity maturation is a result of somatic mutation of Ig heavy and light chain genes induced by AID, followed by selective survival of the B cells that produce the high-affinity antibodies and bind to antigen displayed by FDCs in the germinal centers. Tfh cells also participate in selection of high-affinity B cells.
* Some of the progeny of germinal center B cells differentiate into antibody-secreting plasma cells that migrate to the bone marrow. Other progeny become memory B cells that live for long periods, recirculate between lymph nodes and spleen, and respond rapidly to subsequent exposures to antigen by differentiating into high-affinity antibody secre-tors. The differentiation of activated B cells into plasma cells or memory cells is controlled by the expression of various transcription factors.
* TI antigens are generally nonprotein antigens that induce humoral immune responses without the involvement of helper T cells. Many TI antigens, including polysaccharides, membrane glycolipids, and nucleic acids, are multivalent, can cross-link multiple membrane Ig molecules on a B cell, and activate complement, thereby activating the B cells without T cell help. TLR activation on B cells by microbial products facilitates T-independent B cell activation. TI antigens stimulate antibody responses in which there is limited heavy chain class switching, affinity maturation, or memory B cell generation because these features are largely dependent on helper T cells, which are not activated by nonprotein antigens. However, some T-independent isotype switching can be induced by TLR stimulation by microbes, which may lead to the production of cytokines of the TNF family that activate B cells to induce AID.
* Antibody feedback is a mechanism by which humoral immune responses are downregulated when enough antibody has been produced and soluble antibody-antigen complexes are present. B cell membrane Ig and the receptor on B cells for the Fc portions of IgG, called FcyRIIB, are clustered together by antibody-antigen complexes. This activates an inhibitory signaling cascade through the cytoplasmic tail of FcyRIIB that terminates the activation of the B cell.
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