RESUMEN
Previously, we have shown that IL-21R(-/-) splenocytes ameliorate GVHD as compared with wild-type splenocytes. Here, we investigated whether or not IL-21R(-/-) splenocytes diminish the graft-versus-leukemia (GVL) effect. Surprisingly, IL-21R(-/-) splenocytes efficiently eliminate leukemic cells as well as wild-type splenocytes, suggesting the retention of GVL effects in the absence of IL-21 signaling. To compare the GVL effect between IL-21R(-/-) and wild-type cells, we titrated the number of splenocytes required for the elimination of leukemic cells and found that the threshold of GVL effect was obtained between 5 × 10(5) and 5 × 10(6) with both types of splenocytes. Cotransplantation with CD8-depleted splenocytes but not with purified CD8 T-cells resulted in a significant reduction in anti-leukemic effect of IL-21R(-/-) cells compared with wild-type cells, suggesting that the lack of IL-21 signaling primarily impairs CD4 T-cell rather than CD8 T-cell function and the comparable GVL effect with IL-21R(-/-) bulk splenocytes results from cooperative compensation by CD8 T-cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Efecto Injerto vs Leucemia/inmunología , Interleucinas/inmunología , Leucemia/inmunología , Transducción de Señal/inmunología , Animales , Efecto Injerto vs Leucemia/genética , Humanos , Subunidad alfa del Receptor de Interleucina-21/genética , Subunidad alfa del Receptor de Interleucina-21/inmunología , Interleucinas/genética , Interleucinas/metabolismo , Leucemia/genética , Leucemia/terapia , Ratones , Ratones Noqueados , Transducción de Señal/genéticaRESUMEN
Immunological effects of IL-21 on T, B and natural killer (NK) cells have been reported, but the role of IL-21 in GVHD remains obscure. Here, we demonstrate that morbidity and mortality of GVHD was significantly reduced after BMT with splenocytes from IL-21R(-/-) mice compared with those from wild type mice. To further confirm our observation, we generated a decoy receptor for IL-21. GVHD was again less severe in mice receiving BM cells transduced with the IL-21 decoy receptor than control mice These results suggest that IL-21 critically regulates GVHD, and that blockade of the IL-21 signal may represent a novel strategy for the prophylaxis for GVHD.