Clonal Anergy

T- and B-cell clonal deletion fail to eliminate all autoreactive cells. In the case of T cells, those that recognize self-antigens not expressed in the thymus will eventually be released and will reach the peripheral lymphoid tissues. The causes of B-cell escape from clonal deletion are not as well defined, but they exist nonetheless. Thus, peripheral tolerance mechanisms must exist to ensure that autoreactive clones of T and B cells are neutralized after their migration to the peripheral lymphoid tissues. Clonal anergy is one such mechanism. Clonal anergy can be defined as the process that incapacitates or disables autoreactive clones that escape selection by clonal deletion. Anergic clones lack the ability to respond to stimulation with the corresponding antigen. The most obvious manifestation of clonal anergy is the inability to respond to proper stimulation. Anergic B cells carry IgM autoreactive antibody in their membrane but are not activated as a result of an antigenic encounter. Anergic T cells express TCR for the tolerizing antigen but fail to properly express the interleukin (IL)-2 and IL-2 receptor genes and to proliferate in response to it. Anergy results either from an internal block of the intracellular signaling pathways or from the down-regulating effects exerted by suppressor cells, and it can be experimentally induced after the ontogenic differentiation of immunocompetent cells has reached a stage in which clonal deletion is no longer possible (Singer and Abbas 1994).

There is now ample evidence suggesting that tolerance results from a combination of clonal deletion and clonal anergy. Both processes must coexist and complement each other under normal conditions so that autoreactive clones that escape deletion during embryonic development may be down-regulated and become anergic. Failure of either of these mechanisms may result in development of an autoimmune disease.

Proper stimulation of mature CD4+ T lymphocytes requires at least two signals: one delivered by interaction of the TCR with the major histocompatibility complex (MHC) II-antigen complex and the other delivered by the accessory cell. Both signals require cell-cell contact involving a variety of surface molecules and the release of soluble cytokines. When all of these signals are properly transmitted to the T lymphocyte, a state of activation ensues. Several experiments suggest that the state of anergy develops when TCR-mediated signaling is not followed by co-stimulatory signals. If T lymphocytes are stimulated with chemically fixed accessory cells (which cannot release cytokines or up-regulate membrane molecules involved in the delivery of co-stimulatory signals) or with purified MHC-II-antigen complexes (which also cannot provide co-stimulatory signals), anergy results (Burkly et al. 1990). From the multitude of co-stimulatory pairs of molecules that have been described, the CD28/CTLA-4-B7 family is the most significant in the physiology of T-cell anergy. CD28-mediated signals are necessary for the production of IL-2, which seems to be critical for the initial proliferation of TH0 cells and the eventual differentiation of TH1 cells. If the interaction between CD28 and its ligand is prevented at onset of the immune response, anergy and tolerance ensue. If cytotoxic T-lymphocyte activation molecule-4 (CTLA)-4 is engaged instead of CD28, a down-regulating signal is delivered to the T-lymphocyte. Obviously, a better understanding of the regulatory mechanisms controlling the expression of alternative CD28 ligands is needed for our understanding of how a state of anergy is induced and perpetuated. It is possible that a parallel could be defined for B-cell anergy. The CD40 (B cells)-CD40 ligand (T cells) interaction is critically important for B-cell differentiation. In the absence of CD40 signaling, B cells are easy to tolerize (Rathmell et al. 1996, Thomson 1995).

It is possible to interpret the differences between high-zone and low-zone tolerance as a result of differences in the degree of co-stimulation received by T cells. In high-zone tolerance, the co-stimulatory signals are excessively strong and both T and B cells are down-regulated. Very low antigen doses fail to induce the delivery of co-stimulatory signals to T cells, and low-zone T-cell tolerance ensues (Goodnow 1992).

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