T-CELL HELP AND THE HUMORAL IMMUNE RESPONSE
Antigens can be broadly classified as T-dependent or T-inde-pendent according to the need for T-cell help in the induction of a humoral immune re-sponse. Most complex proteins are T-dependent antigens, while most polysaccharides can elicit antibody synthesis without T-cell help.
It is also clear that T and B lymphocytes cooperating in the inductive stages of an im-mune response do not recognize the same epitopes in a complex immunogen. The mem-brane immunoglobulin of the B cell reacts with surface epitopes expressed on the native antigen, whereas the cooperating T cell recognizes MHC-II–associated peptides derived from the processing of the antigen by accessory cells (a role that can be played both by monocytes/macrophages and by B lymphocytes).
When an immunogen is introduced for the first time into a immunocompetent animal, the antigen is internalized, processed, and presented to helper T cells. Two types of cells can carry out this function:
1. Monocytes, macrophages, and specialized cells such as the dendritic cells found in the lymph node cortex are most effective as antigen-process-ing cells. Their role in the induction of a primary immune response must involve the ingestion and processing of small quantities of antigen opsonized as a con-sequence of complement activation by the alternative pathway or to the binding of C-reactive protein.
2. Activated B lymphocytes may also play the role of APC. Although B cells are uniquely suited for antigen recognition due to the expression of membrane im-munoglobulins able to recognize configurational epitopes in unprocessed anti-gens, their role as APC is believed to require previous activation. B-cell activa-tion induces the expression of co-stimulatory molecules essential for the proper activation of CD4+ T lymphocytes.
Once the membrane immunoglobulin of a B lymphocyte interacts with an epitope of a given immunogen, the complex of surface immunoglobulin-immunogen is internalized, and surface immunoglobulin ceases to be expressed. Although B cells have considerably fewer cytoplasmic enzymes than professional phagocytes (dendritic cells, monocytes, macrophages, and related cells), they are able (at least in vitro) to process the immunogen in an endosomal compartment, where it is degraded into short peptides that become asso-ciated to MHC class II antigens. The MHC-II–oligopeptide complex is then transported to the membrane and presented to CD4+ T cells.
In addition, these same activated B lymphocytes release IL-1 and IL-6 and can engage in co-stimulatory interactions with helper T cells mediated by upregulated membrane molecules . There is a need for high lymphocyte density and intense recircula-tion to fulfill the optimal conditions for T-B cell cooperation, and those are most likely achieved in lymphoid tissues, such as the lymph nodes. The cooperative interaction be-tween T and B lymphocytes is believed to start outside of the primary follicles in the para-cortical area. The subsequent interactions unfold in consecutive phases:
1. Early interaction. At this early phase, T and B cells are not tightly adherent. The initial contact involves molecules used by T cells in their nonspecific interactions with APC, such as CD2, CD4, LFA-1, and ICAM-1. In addition, CD5 molecules on the T cell that bind CD72 molecules on the B cell may also be in-volved at that stage.
2. Firm attachment. Some time after this initial interaction, T and B cells become firmly attached due to the upregulation of several sets of membrane molecules. Some molecules play a predominant role in promoting the stable interaction be-tween the cooperating cells, while others deliver activating signals. As a conse-quence of these multiple interactions, the cells come to close apposition (the in-tercellular distance is reduced to less than 12 nm), and activating signals can be transmitted both to T lymphocytes and B lymphocytes.
Several sets of interacting molecules play significant roles in the signaling of cooperating helper T cells and B cells.
1. Activated CD4+ lymphocytes express increased levels of CD40L able to inter-act with CD40 expressed by B cells. The interaction of CD40 with CD40L in-duces two protein kinase pathways on B lymphocytes. One of the pathways in-volves JAK kinases and STAT transcription factors, while the other pathway involves the MAP kinase and results in the activation of NFkB. Once activated, B cells increase their expression of CD80 (B7-1), expressed at low or unde-tectable levels on resting B lymphocytes, and CD86 (B7-2), constitutively ex-pressed at low levels on resting B cells.
2. As CD80 (B7-1) and CD86 (B7-2) are upregulated, the interaction with their lig-and, the CD28 molecule expressed by T cells, delivers additional activating signals.
3. CD45RO molecules expressed exclusively by memory helper T lymphocytes may interact with CD22 molecules expressed by activated B lymphocytes.
Following activation, B cells undergo mitosis and proliferate and differentiate into anti-body-producing plasma cells. This evolution is associated with migration through different areas of the lymph node.
First the activated B cells separate from the helper T cell and migrate to the denser ar-eas of the follicle, around the germinal centers, where they proliferate with a rapid cycling time of about 7 hours. In 5 days, the antigen-stimulated B-lymphocyte population in a given germinal center increases about 1000-fold. Most resting B cells express IgM and IgD on the cell membrane, and in the initial stages of cell differentiation many cells will produce and secrete IgM antibody, characteristic of the early stages of the primary immune response.
As B cells continue to proliferate and differentiate, recombination genes will be ac-tivated (apparently as a consequence of cytokine-mediated signaling) and class switch takes place. The constant region genes for µ and δ chains are looped out and one of the con-stant region genes for IgG, IgA, or IgE moves into the proximity of the rearranged V-D-J genes . Subsequently, the synthesis of IgM antibody declines, replaced by antibody of the other classes, predominantly IgG. The isotype class switch seems to depend on signals delivered both by cytokines (e.g., IL-4) and by cell-cell interactions involving CD40 and CD40L. The signaling pathways that lead to the activation of the recombination genes and, subsequently, to isotype switch, have yet to be defined.
The functional differentiation of B lymphocytes coincides with migration of the dif-ferentiating B cells and plasmablasts to different territories. First, the dividing B cells mi-grate into the clear areas of the germinal centers and into the mantle zone. Those areas are rich in CD4+ , CD40L+ T cells, which apparently deliver a critical signal to B cells, medi-ated by CD40-CD40L interaction. Once committed to differentiation into antibody pro-duction, the activated B cells differentiate into plasmablasts, which exit the lymph nodes through the medullary cords and migrate to the bone marrow, where they become fully dif-ferentiated, antibody-secreting plasma cells.
In murine models, activated B cells receiving a CD40-mediated signal differentiate either into memory B cells or antibody-producing plasma cells. What determines that B cells differentiate into antibody-producing plasma cells or memory cells is not known. It has been suggested that co-stimulatory signals delivered by IL-2 and IL-10 promote the dif-ferentiation of B memory cells, but this remains to be confirmed. In humans, CD40-medi-ated activating signals must be involved both in the differentiation of IgG-producing plasma cells and of memory B cells. Children born with a defective CD40L gene suffer from an immunodeficiency known as the hyper-IgM syndrome in which B cells cannot switch from IgM to IgG production and no immunological memory is generated.
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