TH-cell recognition of an antigenic peptide-MHC complex sometimes results in a state of nonresponsiveness called clonal anergy, marked by the inability of cells to proliferate in response to a peptide-MHC complex. Whether clonal expansion or clonal anergy ensues is determined by the presence or absence of a co-stimulatory signal (signal 2), such as that produced by interaction of CD28 on TH cells with B7 on antigen-presenting cells. Experiments with cultured cells show that, if a resting TH cell receives the TCR-mediated signal (signal 1) in the absence of a suitable co-stimulatory signal, then the TH cell will become anergic. Specifically, if resting TH cells are incubated with glutaraldehyde-fixed APCs, which do not express B7 (Figure 10-15a), the fixed APCs are able to present peptides together with class II MHC molecules, thereby providing signal 1, but they are unable to provide the necessary co-stimulatory signal 2. In the absence of a co-stimulatory signal, there is minimal production of cy tokines, especially of IL-2. Anergy can also be induced by incubating Th cells with normal APCs in the presence of the Fab portion of anti-CD28, which blocks the interaction of CD28 with B7 (Figure 10-15b).
Two different control experiments demonstrate that fixed APCs bearing appropriate peptide-MHC complexes can deliver an effective signal mediated by T-cell receptors. In one experiment, T cells are incubated both with fixed APCs bearing peptide-MHC complexes recognized by the TCR of the T cells and with normal APCs, which express B7 (Figure 10-15d). The fixed APCs engage the TCRs of the T cells, and the B7 molecules on the surface of the normal APCs crosslink the CD28 of the T cell. These T cells thus receive both signals and undergo activation. The addition of bivalent anti-CD28 to mixtures of fixed APCs and T cells also provides effective co-stimulation by crosslinking CD28 (Figure 10-15e). Well-controlled systems for studying anergy in vitro have stimulated considerable interest in this phenomenon. However, more work is needed to develop good animal systems for establishing anergy and studying its role in vivo.
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