SIGNALS REQUIRED FOR ACTIVATION AND GROWTH OF AUTOIMMUNE LYMPHOCYTES-T

  • 1 January 1984
    • journal article
    • research article
    • Vol. 1  (6) , 347-356
Abstract
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 interleukin 2 (IL 2) activity in vitro. Yet, paradoxically, massive expansion of the T cell pool occurs in vivo. While spleen cells from such mice were 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. Culturing lpr spleen cells with an anti-IL 2 receptor antibody abrogated the mitogenicity of Con A + PMA; on stimulation with Con A + PMA, MRL-lprl/lpr T cells expressed IL 2 receptors, and addition of recombinant IL 2 to the receptor positive population resulted in marked proliferation. By 2-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 and normal T cells. The etiology of the Con A unresponsiveness of MRL-lpr/lpr cells remained to be clarified. 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. These results confirmed that lpr cells had intrinsically normal IL 2 activity and suggested that T cells taken directly from the animal contained or produced mediators which prevented responsiveness to mitogenic lectins. Previously, it was reported that MRL-lpr/lpr mice produced enough interferon (IFN) in vivo to be detectable in the serum. Since IFN is known to inhibit the growth of a variety of cells, the potential role of IFN in the IL 2 defect of autoimmune mice was examined. IFN markedly impaired in vitro responses of cells from normal mice to Con A. Poly (rI:rC), administered to normal mice in doses which produce serologically detectable levels of IFN, generated cells which could abrogate the proliferative response of untreated syngeneic cells to Con A but not to Con A + PMA. Rather than coding for a defect in IL 2 activity, as has been traditionally postulated, the lpr genome may be programmed to provide excessive IFN activity. The IFN, by interfering with normal T cell functions, may thereby play a central role in the etiopathogenesis of autoimmune disease.