Circadian timekeeping in plants increases photosynthesis and productivity. There are circadian oscillations in the abundance of many chloroplast-encoded transcripts, but it is not known how the circadian clock regulates chloroplast transcription or the photosynthetic apparatus. We show that, in Arabidopsis, nuclear-encoded SIGMA FACTOR5 (SIG5) controls circadian rhythms of transcription of several chloroplast genes, revealing one pathway by which the nuclear-encoded circadian oscillator controls rhythms of chloroplast gene expression. We also show that SIG5 mediates the circadian gating of light input to a chloroplast-encoded gene. We have identified an evolutionarily conserved mechanism that communicates circadian timing information between organelles with distinct genetic systems and have established a new level of integration between eukaryotic circadian clocks and organelles of endosymbiotic origin.

During chronic viral infection, persistent exposure to viral Ags leads to the overexpression of multiple inhibitory cell-surface receptors that cause CD8+ T cell exhaustion. The severity of exhaustion correlates directly with the level of infection and the number and intensity of inhibitory receptors expressed, and it correlates inversely with the ability to respond to the blockade of inhibitory pathways. Friend virus (FV) is a murine retrovirus complex that induces acute high-level viremia, followed by persistent infection and leukemia development, when inoculated into immunocompetent adult mice. In this article, we provide conclusive evidence that FV infection results in the generation of virus-specific effector CD8+ T cells that are terminally exhausted. Acute FV-induced disease is characterized by a rapid increase in the number of virus-infected erythroblasts, leading to massive splenomegaly. Most of the expanded erythroblasts strongly express programmed death ligand-1 and MHC class I, thereby creating a highly tolerogenic environment. Consequently, FV-specific effector CD8+ T cells uniformly express multiple inhibitory receptors, such as programmed cell death 1 (PD-1), T cell Ig domain and mucin domain 3 (Tim-3), lymphocyte activation gene-3, and CTLA-4, rapidly become nonresponsive to restimulation and are no longer reinvigorated by combined in vivo blockade of PD-1 and Tim-3 during the memory phase. However, combined blockade of PD-1 and Tim-3 during the priming/differentiation phase rescued FV-specific CD8+ T cells from becoming terminally exhausted, resulting in improved CD8+ T cell functionality and virus control. These results highlight FV’s unique ability to evade virus-specific CD8+ T cell responses and the importance of an early prophylactic approach for preventing terminal exhaustion of CD8+ T cells.

Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 gene influences the persistence of viremia and production of virusneutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3-or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.Several host genetic factors control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The recovery from Friend virus 3 gene (Rfv3) was identified as a host gene locus that affects the persistence of viremia and development of virus-specific antibody (Ab) responses upon Friend virus (FV) infection (5). FV is the pathogenic retrovirus complex composed of replication-competent Friend murine leukemia virus (F-MuLV) and the defective spleen focus-forming virus (SFFV). The product of the SFFV env gene, gp55, forms a complex with the erythropoietin receptor and the short form of the hematopoietic-cell-specific receptor tyrosine kinase (STK), and this interaction induces the growth and terminal differentiation of erythroid progenitor cells, causing increased hematocrit values and massive splenomegaly. The resultant increase in targets of FV integration consequently causes the emergence of mono-or oligoclonal erythroleukemia through insertional activation of transcription factors or disruption of a tumor suppressor gene (15,29,34). Mice of the C57BL background possess mutations in the intron of the Stk gene and lack expression of the short-form STK, resulting in resistance to SFFV-induced splenomegaly (37).This host factor was first described as polymorphisms at the Fv2 locus, with the resistance allele found in C57BL m...

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