Hypo-active variant of IL-2 and associated decreased T cell activation contribute to impaired apoptosis in autoimmune prone MRL mice

Abstract

Apoptosis of activated lymphocytes is crucial to the maintenance of immune homeostasis and self-tolerance, as demonstrated by the well-known autoimmune MRL/pr mouse lacking the death receptor Fas. However, even MRL+/+ activated T cells have a resistance to Fas-mediated apoptosis as compared to T cells from the non-autoimmune FVB/N strain. To understand the molecular mechanisms underlying these strain differences, we studied biochemical characteristics of T cells upon activation. Compared to FVB/N T cells, MRL T cells under-expressed procaspase-3 but over-expressed FLIPL. In addition, up-regulation of Bcl-X-L, IL-2, and CD25 was diminished in MRL cells, suggesting inadequate T cell activation. Upon finding that MRL, like other autoimmune strains NOD and SJL, has a hypo-active variant of the IL-2 gene, we added wild-type murine recombinanat (mr)IL-2 during activation. Exogenous mrIL-2 restored MRL apoptosis to the level of FVB/N; in addition, expression of procaspase-3, and FLIPL, Bcl-X-L and CD25 was normalized. These results suggest that defective MRL T cell activation, in part due to hypo-active IL-2, underlies the impaired apoptosis of this strain. In addition, the hypo-active variant of IL-2 shared among autoimmune strains may, by causing diminished cell activation and cell death, predispose these strains to develop autoimmune disease.