NORMAL CLONAL EXPANSION BUT IMPAIRED FAS-MEDIATED CELL-DEATH AND ANERGY INDUCTION IN INTERLEUKIN-2-DEFICIENT MICE

Despite a normal development of all major lymphoid subsets, with time, interleukin-2 (IL-2)-deficient mice develop a fatal immunopathology. The disease phenotype is characterized by lymphoadenopathy, splenomega ly, T cell infiltration of various organs, overproduction of a number of cytokines and autoantibody formation. Phenotypically, CD4(+) and CD 8(+) T cells exhibit features characteristic of antigenically experien ced cells. The accumulation of cells with a memory phenotype together with the previous suggestion of an involvement of IL-2 in the terminat ion phase of immune responses prompted us to study the fate of superan tigen-reactive T cells in IL-2-deficient mice in comparison to their I L-a-producing littermates. We show that expansion in vivo of CD4(+) an d, to a lesser extent, CD8(+)T cells reactive to the superantigens sta phylococcal enterotoxin A and B (SEA and SEB) proceeds normally in the absence of IL-2, but that fewer CD4(+) cells are subsequently deleted . The residual superantigenreactive cells fail to become anergic as me asured by proliferation in vitro in response to the same superantigen. T cell blasts generated in vitro from lymph node cells of IL-2-defici ent mice by superantigen stimulation in the absence of exogenous IL-2 also fail to become anergic. In contrast to cells from IL-2-producing littermates, they do not exhibit Fas-induced apoptosis when cultured o n anti-Fas antibody-coated plates, although Fas expression by IL-2-def icient cells is normal or even elevated compared to the IL-2-producing control cells. The data suggest that activation of T cells in the abs ence of IL-2 fails to generate a signal which is necessary to activate the apoptotic pathway and thus leads to an accumulation of antigen-ex perienced cells and the chronic inflammatory responses observed in IL- 2-deficient mice.