Signals required for activation and growth of autoimmune T lymphocytes.
T cell growth is principally regulated by the lymphokine interleukin 2 (IL 2). Following induction of IL 2 receptors, immunologically normal cells proliferate and will continue to do so until the level of IL2 becomes limiting. Spleen cells from autoimmune-prone mice and peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE), however, are severely deficient in their capacity to both produce and respond to IL 2 following a challenge with mitogenic lectins. These observations have suggested the possibility that IL 2 may not function as a T cell growth factor in the autoimmune milieu. In order to determine the requirements for T lymphocyte proliferation in autoimmunity, MRL-lpr/lpr mice were studied. Spleen cells from this murine model of lupus exhibit profound defects in IL 2 activity in vitro. Yet, paradoxically, massive expansion of the T cell pool occurs in vivo. While spleen cells from such mice were, indeed, unable to produce IL 2 or to proliferate when stimulated with concanavalin A (Con A), the combination of Con A plus the comitogen phorbol myristate acetate (PMA) engendered substantial IL 2 production and normal cellular proliferation. Since numerous lymphokines are produced when cells are cultured with Con A + PMA, it remained to be shown that IL 2 was, in fact, the responsible growth factor. We found that culturing lpr spleen cells with an anti-IL 2 receptor antibody abrogated the mitogenicity of Con A + PMA; that on stimulation with Con A + PMA, MRL-lpr/lpr T cells expressed IL 2 receptors, and that addition of recombinant IL 2 to the receptor positive population resulted in marked proliferation. Furthermore, by two-color flow cytometric analysis it was demonstrated that T cells which bear the phenotype of those which undergo clonal expansion in the lpr were capable of expressing IL 2 receptors. Thus, IL 2 can be utilized as a growth factor, in vitro, by autoimmune as well as normal T cells. The etiology of the Con A unresponsiveness of MRL-lpr/lpr cells remained to be clarified. We observed that, in contrast to the refractoriness of fresh cells, lymph node cells which had been cultured for several days in the absence of antigenic stimulation were capable of expressing IL 2 receptors and of proliferating on exposure to Con A. Using flow cytometry it was found that selective expansion of a subset of phenotypically "normal" lymphocytes had not occurred.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D007372:Interferons / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*
D007376:Interleukin-2; D008934:Mitogens; D015375:Receptors, Interleukin-2; D007372:Interferons