CYTOKINE AND T-CELL SUBSET ABNORMALITIES IN IMMUNODEFICIENT WASTED MICE

Wasted mice bear an autosomal recessive mutation (wst/wst) that manifests itself in neurologic abnormalities, immunologic deficiency, and faulty DNA repair evident by 21 days of age. The immunodeficiency is characterized by a reduction in the thymus-to-body weight ratio, low levels of IgA plasma cells at secretory sites, and increased sensitivity of T-cells to the killing effects of ionizing radiation. Experiments were 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 littermates. Further studies of T-cell subpopulations with thymocytes revealed normal percentages of CD4(+) and CD8(+) cells in wst/wst mice; however, double-labeling experiments showed that CD8(+) cells were predominantly CD4(-) in wst/wst mice, whereas in controls most CD8(+) cells also expressed CD4(+). Mesenteric lymph node T-cell subpopulations were similar in wasted and control mice. Because cytokines play a significant role in the regulation of the immune response and also interact with a variety of cellular systems, we examined the expression of different cytokine and related genes (IL1, IL2, IL2R, TNF, IL5, gamma-interferon, 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 revealed a deficiency of IL5 mRNA in thymus and spleen, decreased expression of IL2R in thymus (but not spleen), increased expression of IL1 in spleen (but not thymus), and increased expression of IL2, gamma-interferon, and beta-TGF in both spleen and thymus, relative to controls. Expression of TNF mRNA in lymphoid tissues was unaffected by the wasted mutation. These results suggest a role for cytokine imbalance in the pathogenesis of the immunodeficiency and other abnormalities of wasted mice.