PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.

In T lymphocytes, p38 MAP kinase (MAPK) regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative T cell receptor (TCR) activation pathway. Here we show that senescent human T cells lack the canonical and alternative pathways of p38 activation, but spontaneously engage the metabolic master regulator AMPK to trigger p38 recruitment to the scaffold TAB1 causing p38 auto-phosphorylation. Signaling via this pathway inhibits telomerase activity, T cell proliferation and expression of key components of the TCR signalosome. Our findings identify an unrecognized mode of p38 activation in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (‘intra-sensory’ pathway). The proliferative defect of senescent T cells is reversed by blocking AMPK-TAB1-dependent p38 activation.

The engineering of a full-length infectious cDNA clone and a functional replicon of the severe acute respiratory syndrome coronavirus (SARS-CoV) Urbani strain as bacterial artificial chromosomes (BACs) is described in this study. In this system, the viral RNA was expressed in the cell nucleus under the control of the cytomegalovirus promoter and further amplified in the cytoplasm by the viral replicase. Both the infectious clone and the replicon were fully stable in Escherichia coli. Using the SARS-CoV replicon, we have shown that the recently described RNA-processing enzymes exoribonuclease, endoribonuclease, and 2-O-ribose methyltransferase were essential for efficient coronavirus RNA synthesis. The SARS reverse genetic system developed as a BAC constitutes a useful tool for the study of fundamental viral processes and also for developing genetically defined vaccines.The etiologic agent causing severe acute respiratory syndrome (SARS) is a novel coronavirus (CoV) (8,10,(16)(17)(18)21). This virus causes a life-threatening respiratory disease for which no fully efficacious therapy is available. SARS-CoV is a member of group 2 of the Coronaviridae family within the order Nidovirales (13), which is composed of enveloped, singlestranded, positive-sense RNA viruses relevant in animal and human health (5, 9). Two-thirds of the 29.7-kb SARS-CoV genome carries the replicase gene, which comprises two overlapping open reading frames, ORF 1a and ORF 1b, the latter being translated by a ribosomal frameshift mechanism (29). Translation of both ORFs results in the synthesis of two polyproteins that are processed by viral proteinases to release the components of the replication-transcription complex (36,37). Besides containing RNA-dependent RNA polymerase, RNA helicase, and proteases (4,12,15,23,37), which are all common to positive-strand RNA viruses, the CoV replicase was recently predicted to contain a variety of RNA-processing enzymes that are extremely rare or absent in other RNA viruses, including endoribonuclease (NendoU), 3Ј-to-5Ј exoribonuclease (ExoN), 2Ј-O-ribose methyltransferase (2Ј-O-MT), ADP ribose 1ЈЈ-phosphatase, and, in a subset of group 2 coronaviruses, cyclic phosphodiesterase (25, 36). These enzymatic activities might be involved in the replication of the largest known RNA virus genome and in the production of an extensive set of 5Ј-and 3Ј-coterminal subgenomic RNAs (11,14,25,36).The study of CoV molecular biology has been profoundly advanced by the recent construction of full-length cDNA clones (3,6,26,27,(32)(33)(34) and self-replicating RNAs, or replicons (2,28,30). Due to the large size of the CoV RNA genome and the instability of some CoV replicase gene sequences in bacteria, cDNA clones and replicons have been engineered using bacterial artificial chromosomes (BACs) (3), in vitro ligation of CoV cDNA fragments (32), and vaccinia virus as a vector for the propagation of CoV full-length cDNAs (27). Recently, a SARS-CoV full-length cDNA clone has been generated by the approach of using the in vitro li...