CYTOKINE AND T-CELL SUBSET ABNORMALITIES IN IMMUNODEFICIENT WASTED MICE

Wasted mice bear an autosomal recessive mutation (wst/wst) that manife sts itself in neurologic abnormalities, immunologic deficiency, and fa ulty DNA repair evident by 21 days of age. The immunodeficiency is cha racterized by a reduction in the thymus-to-body weight ratio, low leve ls of IgA plasma cells at secretory sites, and increased sensitivity o f T-cells to the killing effects of ionizing radiation. Experiments we re designed to examine measures of T-cell activity in wasted mice. The initial experiments established that wst/wst mice have percentages of thymic and splenic Thy1(+) cells equivalent to those of control litte rmates. Further studies of T-cell subpopulations with thymocytes revea led normal percentages of CD4(+) and CD8(+) cells in wst/wst mice; how ever, double-labeling experiments showed that CD8(+) cells were predom inantly CD4(-) in wst/wst mice, whereas in controls most CD8(+) cells also expressed CD4(+). Mesenteric lymph node T-cell subpopulations wer e similar in wasted and control mice. Because cytokines play a signifi cant role in the regulation of the immune response and also interact w ith a variety of cellular systems, we examined the expression of diffe rent cytokine and related genes (IL1, IL2, IL2R, TNF, IL5, gamma-inter feron, beta-TGF) in lymphoid tissues from wasted mice as well as from littermate and parental controls. Studies of RNA from lymphoid tissues of wasted mice using dot blot and Northern blot hybridizations reveal ed a deficiency of IL5 mRNA in thymus and spleen, decreased expression of IL2R in thymus (but not spleen), increased expression of IL1 in sp leen (but not thymus), and increased expression of IL2, gamma-interfer on, and beta-TGF in both spleen and thymus, relative to controls. Expr ession of TNF mRNA in lymphoid tissues was unaffected by the wasted mu tation. These results suggest a role for cytokine imbalance in the pat hogenesis of the immunodeficiency and other abnormalities of wasted mi ce.