title: Interleukin-2, a pro-autoimmune lymphokine that interferes with post-deletional tolerance.
abstract: Various complementary mechanisms arranged in a fail-safe hierarchy impede the immune system from launching auto-aggressive attacks, namely intrathymic or post-thymic clonal deletion, anergy, and immunosuppression. Both epidemiological and clinical evidence demonstrates that interleukin-2 (IL-2) may exert a pro-autoimmune effect. Thus, IL-2 reverses immunological tolerance in determined in vitro or in vivo circumstances, is produced at abnormally high levels in certain autoimmune diseases, and induces organ-specific autoimmune lesions when administered to patients. To unravel the molecule and cellular mechanisms responsible for the pro-autoimmune nature of IL-2, our group has employed a recombinant hIL-2 vaccinia virus construct (IL-2. VV) as a self-replicating IL-2-releasing device that may be administered as a source of exogenous IL-2 to experimentally manipulated mice. IL-2 does not interfere with clonal deletion of potentially autoreactive T cells in the thymus since application of IL-2. VV to young mice fails to augment the frequency of T cells bearing 'forbidden' T cell receptor (TCR) V beta gene products (i.e. T cells that recognize endogenous retroviral superantigens). Along the same line, IL-2. VV does not reverse the clonal deletion in male mice bearing a male-specific transgenic alpha/beta TCR that undergo depletion of CD4+ CD8+ thymocytes, nor does it abolish post-thymic clonal deletion of V beta 8+ T cells reactive with the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB). In contrast with its incapability to abolish intra- and post-thymic elimination of T cells with unwarranted specificities, IL-2 abrogates anergy of T cells. Non-deleted, 'forbidden' T cells from congenitally athymic or neonatally thymectomized mice, under normal circumstances anergic, become responsive to TCR-triggering and mediate a systemic autoimmune syndrome upon IL-2. VV treatment. Thus, IL-2 appears to interfere with T cell tolerance at a post-deletional stage, reversing functional non-responsiveness and enabling non-deleted T cells that bear a potentially autoreactive TCR repertoire to cause manifest autoimmunity.
authors.affiliation: Centro de Biología Molecular (CSIC), Universidad Autónoma de Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: C
authors.initials: C
authors.lastname: Martínez
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics / Q000276:immunology; D008817:Mice, Mutant Strains / Q000235:genetics / Q000276:immunology; D008822:Mice, Transgenic; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology
chemical_list: D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell