Polyethylene glycol-modified IL-2 abrogates superantigen-induced anergy without affecting peripheral clonal deletion in vivo

As compared with the native molecule, recombinant human interleukin-2 that is modified by covalently attached polyethylene glycol residues (IL-2-PEG) exhibits a markedly enhanced half-life in vivo, thus facilitating its biological evaluation. We have characterized the effect of IL-2-PEG on the Staphylococcus aureus enterotoxin B (SEB)-induced tolerance of peripheral SEB-reactive (Vβ8⁺) T cells. Treatment with sublethal doses of IL-2-PEG does not modulate (inhibit or enhance) the SEB-triggered apoptosis and deletion of Vβ8⁺ T cells. In contrast, in vivo treatment with IL-2-PEG partially abolishes the SEB-triggered anergy of Vβ8⁺ T cells, i.e., the failure to proliferate in response to SEB in vitro. To abolish SEB-triggered anergy, IL-2-PEG must act for an extended period in vivo; short term treatment in vivo (2 days) or exposure of anergic T cells to IL-2 in vitro fails to reconstitute proliferative responses. Moreover, the effect of in vivo treatment with IL-2-PEG on lymphokine production by anergic T cells is partial. IL-2-PEG restores IL-4-dependent autocrine proliferation in response to SEB but does not reestablish defective IL-2 production. These data are compatible with the notion that IL-2 is a regulator of postdeletional rather than deletional T cell tolerance.