NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

There is strong evidence that Trp catabolism and IDO1 expression in dendritic cells, which have a myeloid lineage, are important for the suppression of T-cell responses and the promotion of immune tolerance [73] . The reduction of extracellular Trp, the generation of metabolites via the kynurenine pathway and the signaling function of tyrosine-phosphorylated IDO1 all contribute to immunosuppression and protection against autoimmune disease and allograft rejection by inhibiting the proliferation of T cells and NK cells and promoting autophagy and anergy [74, 75] . The strong down-regulation of Trp catabolism caused by elevated Ap 4 A would therefore be expected to promote T-cell responses and suppress tolerance. This is consistent with the up-regulation of adaptive immune functions in NuKO cells predicted by IPA 1 (Table 4 ). Furthermore, overexpression of IMPACT, an inhibitor of the GCN2-kinase (EIF2AK4) stress-signaling pathway that represses translation and proliferation in response to amino acid starvation, protects T-cells from Trp depletion [76] . IMPACT is up-regulated 13-fold in NuKO cells (S3 Table) and this would contribute further to the promotion of T-cell responses if reproduced in T cells.