No abstract

Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7Ra) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7Ra null -induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7Ra signaling with the p53 pathway, we generated IL-7Ra null p53 null (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Ra signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Ra signaling in IL-7-dependent p53 null cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Ra during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokinemediated survival signals and T-cell lymphomagenesis. Interleukin-7 (IL-7) is an essential and nonredundant cytokine for T-cell development. 1 Humans and mice deficient in IL-7 receptor (IL-7Ra) incur severe T-cell development defects, manifesting SCID. [1][2][3][4] Early studies have shown that unbalanced survival signals of the Bcl-2 family members contribute to the impaired thymopoiesis in IL-7Ra deficiency. 1 Nevertheless, ectopic expression of Bcl-2 or inactivation of Bcl-2-associated X protein in IL-7Ra null mice only partially rescues the thymopoietic defect, 5-7 suggesting the possible involvement of the other pathways.The tumor-suppressor p53 is a crucial transcription factor in controlling the cell cycle and apoptosis of cells under genotoxic stresses. 8 Early studies show that p53 participates in critical thymopoiesis checkpoints related to T-cell receptor rearrangement and DNA damage repair. 9-11 Emerging evidence suggests that p53 is a crucial regulatory factor of normal physiological processes, such as maintenance of stem cell state, development, tissue homeostasis, and autoimmunity. [12][13][14][15] We hypothesized that p53 activation also contributes to the apoptosis and impaired thymopoiesis in IL-7Ra deficiency. However, the interplay between the IL-7/IL-7Ra signaling and the p53 pathway has not been demonstrated.To decipher the potential genetic association of the IL-7Ra signaling with the p53 pathway, we crossed IL-7Ra null mice with p53 null mice. Intriguingly, genetic deletion of p53 in IL-7Ra null background (IL-7Ra null p53 null , DKO mice) n...