Superantigen-reactive T cells that display an anergic phenotype in vitro appear functional in vivo

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Abstract
Clonal deletion and/or inactivation establishes tolerance to self antigens. Endogenous and exogenous (bacterial) superantigens, like the staphylococcal enterotoxlns, induce ligand-specific clonal anergy in vivo and thus are believed to mirror aspects of post-thymic tolerance mechanisms in mature peripheral T cells. Here we analyzed the level of anergy of ligand-responsive Vβ8+ T cells from staphylococcal enterotoxin B (SEB)-primed mice in vivo and in vitro. Upon in vitro restimulation with SEB, CD4+Vβ8+ and CD8+Vβ8+ T cells failed to produce IL-2. However, functional IL-2 receptors were triggered, since supplementation with IL-2 induced clonal growth in virtually all CD4+Vβ8+ and CD8+Vβ8+ T cells as determined by limiting dilution analyses. Thus in vitro unresponslveness of lymphocytes from SEB-primed mice reflects the inability of SEB-reactlve Vβ8+ T cells to produce IL-2. Surprisingly, anergy as defined in vitro was at variance with that in vivo. Following further challenge with SEB, systemic and acute lymphokine production (Including IL-2 and tumor necrosis factor) occurred with almost identical peak values and kinetics to primary in vivo responses, and D-galactosamlne-sensltlzed mice succumbed to lethal shock. Polymerase chain reaction analyses revealed that CD4+Vβ8+ expressed IL-2-specific mRNA in vivo upon restimulatlon with SEB. While lymphokine production and expression of the IL-2 receptor was similar to the response to in vivo primary stimulation, only CD8+Vβ8+ T cells expanded clonally upon reintroductlon of SEB in vivo. Hence primed Vβ8+ T cells challenged with SEB display in vitro anergy yet in vivo responsiveness, at least in part. We conclude that the state of anergy is reversible, dependent upon the quality of activation signals provided in in vivo rather than in in vitro culture conditions.

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