Sites of peripheral tolerance induction

It is clear that the B cell repertoire is generated in two phases and that tolerance induction must occur at both levels: that of the immature B cell in the bone marrow and later in the periphery in the lymph nodes and spleen. Indeed, this can occur in the latter case both at initial antigen contact (in the absence of costimulation), as well as in the germinal centers during somatic hypermutation before a secondary response (see below). Similarly, while T cell repertoire development goes through positive and negative selection in the thymus, there must be some degree of regulation as peripheral tolerance in various nodes in the body.

The lack of costimulatory molecules on certain cells in the periphery that may be induced to express class II MHC antigens (e.g. by viral infection and interferon production) and present endogenous peptides makes these cells excellent candidates for tolerogenic APCs. Such 'nonprofessional' APCs could present antigenic peptides to T cells virtually anywhere they arise in the body, assuming a reasonable lymphatic or capillary access to those tissues. It is most likely, however, that this presentation occurs in the lymph nodes especially if resting B cells are the presenting APCs. In some cases, immature (less differentiated) dendritic cells could subserve this same function in the white pulp periarteriolar lymphatic sheaths (PALS) in the spleen or the paracortex of the peripheral nodes. It is not clear whether this process occurs elsewhere (such as in mucosal tissues). Suffice it to say that oral exposure to antigens leads to presentation in the gut and preferential skewing of responsiveness to TH2, due for example to local production of transforming growth factor |3 (TGF(3). At the systemic level, this may be expressed as peripheral Th1 tolerance or even suppression. It is likely that this reflects differential cytokine profiles as a consequence of alternative antigen presentation pathways, although the mechanism is not known. In addition, the potential for peripheral deletion to occur in tissues with high levels of Fas ligand (FasL;

such as in privileged sites such as the eye or testis) needs to be considered.

An elegant model system to examine specific niches in which peripheral tolerance occurs was described by Goodnow and colleagues, using the HEL/anti-HEL transgenic model system. In one situation, they used heavy-chain-only transgenic mice so that the rearranged heavy chain could pair with endogenous light chains in the peripheral pool. This gave rise to HEL-binding B cells of various affinities but at a high enough frequency to be detected in vivo. By crossing these Ig receptor transgenic animals with HEL-producing mice, they could determine the relationship between affinity, antigen concentration and the fate of these HEL-specific B cells in the periphery. Their studies not only confirmed this relationship, they also showed that there was a competition between the transgenic 'autoreactive' B cells and the endogenous repertoire for space. That is, if mice contained 100% transgenic B cells, their tissue distribution was similar to B cells in normal mice even when the autoantigen (soluble HEL) was plentiful. But if normal B cells were in excess and antigen was present, these cells failed to enter the follicles in the lymph nodes. Thus, there is a gate, so to speak, that prevents autoreactive B cells (exposed to antigen) from entering the follicles and forming germinal centers. This makes sense since the germinal centers are sites of extensive proliferation and the potential to undergo somatic hypermutation, would be a dangerous event for the host in terms of forming high-affinity autoantibodies.

How does the 'gatekeeping' occur? One likely mechanism is via Fas and Fas ligand. Data from the same group show that FasL on T cells may be acting to delete those B cells that have upregulated their surface expression of Fas, for example by CD40 interaction. Curiously, binding to membrane immunoglobulin M has been shown by Rothstein's group to block susceptibility of those B cells in terms of their susceptibility to undergo a FasL-mediated death signal. This creates a dynamic battle in which antigen-specific and nonantigen-specific signals determine the fate of B cells to survive in a peripheral tolerance pathway depending on which signals predominate, as well as when and where they are delivered as antigen-spe-cific cells sojourn in a lymph node.

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