Lymph Nodes And Spleen

CD4' or CD8*T cells (Single positive T cells)

Anergy; deletion: suppression

Figure 1 Schematic representation of the pathways of B and T cell tolerance. Once rearrangement of Ig genes occurs in pre-B cells in the bone marrow and IgM is expressed, these early IgM-positive B cells are sensitive to tolerance via both deletional and anergic mechanisms, depending on the nature of the antigen. Following maturation, lymphocytes migrate to the periphery (lymph node and spleen), where anergy, deletion and perhaps suppression act as tolerance mechanisms. In both cases, cognate interaction with T cells and the deliverance of costimulation and lymphokine signals may overcome tolerance induction and lead to antibody formation, including autoantibodies. Similarly for T cells, maturing CD4~, CD8 immature T cells are deleted in the thymus, but peripheral T cells may undergo a tolerogenic mechanism leading to an anergic state of apoptosis when exposed to peptides in the absence or costimulation.

negative in the mature T cell pool, but possess V,.^.,-positive immature lymphocytes. This suggests that expression of I-E leads to deletion of T cells bearing a particular TCR-VP as they transit to a mature stage.

In analogy to this process in T cells, the B cell repertoire is generated by V gene arrangements during development. Thus, immunoglobulin H and L chains rearrange in pre-B cells in the marrow to give clones of antigen-specific B cells expressing, initially, immunoglobulin M (IgM). In B cells, however, it has been harder to obtain direct evidence for a deletional event for tolerance since there is no predominant usage of a particular V region in these cells. Nonetheless, it has been assumed that immature B cells with rearranged receptors binding self antigens with high affinity are clonally deleted based on data from three systems: the elimination of B cells by anti-IgM treatment of neonatal mice, the antireceptor-induced death of immature B cell lymphomas and a loss of specific B cells in transgenic mice expressing IgM receptors for self MHC antigen. In the last system, Nemazee and colleagues created transgenic mice in which a large number of the B cells bore IgM receptors which were specific for the membrane class I histocompatibility antigen, H-2Kk. When bred to an H-2k mouse to induce tolerance in these anti-H-2Kk-specific B cells, the IgM-transgenic cells were deleted at an immature stage. It is worth noting that this deletional mechanism may depend on the nature of the antigen (membrane versus soluble) or on the maturity of the B cells when first exposed to tol-erogen (see below).

Further data from the laboratories of Nossal and Scott and their colleagues showed that mice rendered tolerant as adults still possessed B cells with free receptors for the tolerated antigen. These were not cells of low affinity, as is often observed with anti-self-reactive B cells in humans. Rather, these were high-affinity cells which were simply anergic to stimulation by antigen and appeared to be blocked at the G^S boundary of the cell cycle. More definitive evidence came from another transgenic model, this time one in which all B cells expressed IgM and IgD receptors for a peptide from hen egg lysozyme (HEL). When these mice are bred to lysozyme-trans-genic animals, tolerance to HEL is produced. Interestingly, normal numbers of lysozyme-reactive B cells were still present in these double transgenic mice. However, their now anergic (tolerant) B cells had an altered phenotype: they had lost most of their IgM yet retained membrane IgD. This system differs from the deletional model above in terms of both the nature of the antigen and the fact that target B cells express both IgM and IgD, that is, they are mature B cells. More recent experiments suggest that a membrane form of lysozyme causes deletion in anti-HEL transgenics, regardless of IgM/IgD isotype expression, and that this can occur as anergic B cells traverse into the follicles of the nodes. Additional data with another transgenic model suggest that supercrosslinking of transitional cells with IgM and little or no IgD led to deletion. Thus, it appears that multiple pathways for B cell tolerance are probably due to the diversity of antigens that can be considered 'self' and the fact that cells may be exposed to tolerogens at different matu rational stages.

Furthermore, there must be mechanisms to assure-that potential antiself activities that arise from somatic mutation during an immune response are silenced. Evidence from Klinman's laboratory suggests that secondary lineage B cells indeed pass through a 'tolerance susceptible window' after the initiation of an immune response. This would ensure that potentially high-affinity cells were eliminated from the repertoire, either functionally or physically.

Additional experimental data suggest that a form of clonal anergy may also be induced in T, as well as B, cells. Schwartz and his collaborators demonstrated that interleukin 2 (IL-2)-producing CD4' T cell helper (TH1) clones were rendered anergic if exposed to an 'inert' antigen-MHC complex such as fixed macrophages, presumably due to the lack of costimulatory second signals provided by viable, professional antigen-presenting cells (APCs). These anergic T cells fail to produce IL-2 when subsequently appropriately stimulated. Similar results have been reported by Gilbert and Weigle for TH2 helper cells treated in the same way and later measured for their functional capacity to help B cells produce antibody.

How do we explain these disparate results in terms of anergy versus deletion? As stated above, one possibility with respect to B cell tolerance is that different antigens were involved, some soluble and others membrane bound. Alternatively, the maturity of the target B cell (IgM expressing B cells are deleted versus IgM + IgD-bearing cells are rendered anergic) could be an explanation. Indeed, with respect to T cell tolerance, there are clear differences in mechanisms and maturational states between double-positive immature thymocytes and mature Tnl clones, the former being 'deletable', the latter becoming anergic. Moreover, further control pathways for clonal expansion may result in deletion of reactive clones via a Fas-dependent pathway. Thus, the mechanism of tolerance may depend both on the maturity or subset of target cells, as well as the nature of the antigen.

In all cases, therefore, one unifying tenet occurs: exposure to antigen at an inappropriate stage of development or in the absence of costimulation leads to tolerance. Provision of a positive costimulatory signal often overcomes the initial negative signal.

Where does suppression fit into all of this? Fifteen years ago, the activity of suppressor T cells in experimental tolerance systems was under intense investigation. The difficulty in cloning these T cells, as well as the lack of strong molecular evidence on the nature of their TCR, has made it difficult to analyze the activity of these cells. Recent data suggest, however, that at least some cells with suppressive properties bear a normal CD3-linked TCR complex. Indeed, it appears that under certain circumstances normal T

cell clones can effect suppression of B cell differentiation or other T cell activity. Thus, THI cells secreting interferon y or lymphotoxin (TNF0) may-inhibit B cell differentiation whereas T,,2 clones may be directly cytotoxic for antigen-presenting cells displaying peptide + class II MHC on their surface. However, it is now clear that not all self antigens are tolerated via the same mechanism, a conclusion which makes teleological sense due to the variety of antigens and their distribution and concentration in the body.

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