Volume 537 Number 7620

Editorials

News

News Features

Secrets of life in the soil p.298

Diana Wall has built a career on overturning assumptions about underground ecosystems. Now she is seeking to protect this endangered world.

doi: 10.1038/537298a

News & Views

Extraordinary world p.310

The isotopic compositions of objects that formed early in the evolution of the Solar System have been found to be similar to Earth's composition — overturning notions of our planet's chemical distinctiveness. See Letters p.394 & p.399

doi: 10.1038/537310a

Teenage tetrapods p.311

Bone analysis of aquatic tetrapods from around the time when these four-limbed vertebrates began to move onto land reveals that the large specimens were only juveniles, raising questions about how these animals developed. See Letter p.408

doi: 10.1038/nature19432

Cytotoxic T cells that escape exhaustion p.312

T cells of the immune system mount antiviral responses, but if a response fails, a chronic viral infection can develop. It now seems that a T-cell subset in lymphoid immune tissues can control chronic infection. See Letters p.412 & p.417

doi: 10.1038/nature19428

Geography matters for Arabidopsis p.314

A free database describes genome sequences, gene expression and molecular modifications to DNA for more than 1,000 Arabidopsis thaliana plants, providing valuable information on the complex history and current variation of this species.

doi: 10.1038/nature19466

Dietary protection for genes p.315

Nanocrystalline alloys have excellent low-temperature mechanical strength but poor high-temperature resistance to creep — deformation due to continuous stress. An alloy has been made that overcomes this problem. See Letter p.378

doi: 10.1038/537315a

Dietary protection for genes p.316

Dietary restriction is known to extend lifespan in many species. It has now been shown to reduce DNA damage and extend lifespan in mice modelling human DNA-repair disorders. See Letter p.427

doi: 10.1038/nature19427

Articles

Letters

A radio-pulsing white dwarf binary star p.374

Observations of a white dwarf/cool star binary that emits from X-ray to radio wavelengths, AR Sco, reveal a close binary with a 3.56-h period, pulsing in brightness with a period of 1.97 min; these pulses are so intense that the optical flux of AR Sco can increase by a factor of four within 30 s, and the pulsing is detectable at radio frequencies.

doi: 10.1038/nature18620

A nucleosynthetic origin for the Earth’s anomalous 142Nd composition p.394

A long-standing paradigm assumes that the chemical and isotopic compositions of many elements in the bulk silicate Earth are the same as in chondrites. However, the accessible Earth has a greater 142Nd/144Nd ratio than do chondrites. Because 142Nd is the decay product of the now-extinct 146Sm (which has a half-life of 103 million years), this 142Nd difference seems to require a higher-than-chondritic Sm/Nd ratio for the accessible Earth. This must have been acquired during global silicate differentiation within the first 30 million years of Solar System formation and implies the formation of a complementary 142Nd-depleted reservoir that either is hidden in the deep Earth, or lost to space by impact erosion. Whether this complementary reservoir existed, and whether or not it has been lost from Earth, is a matter of debate, and has implications for determining the bulk composition of Earth, its heat content and structure, as well as for constraining the modes and timescales of its geodynamical evolution. Here we show that, compared with chondrites, Earth’s precursor bodies were enriched in neodymium that was produced by the slow neutron capture process (s-process) of nucleosynthesis. This s-process excess leads to higher 142Nd/144Nd ratios; after correction for this effect, the 142Nd/144Nd ratios of chondrites and the accessible Earth are indistinguishable within five parts per million. The 142Nd offset between the accessible silicate Earth and chondrites therefore reflects a higher proportion of s-process neodymium in the Earth, and not early differentiation processes. As such, our results obviate the need for hidden-reservoir or super-chondritic Earth models and imply a chondritic Sm/Nd ratio for the bulk Earth. Although chondrites formed at greater heliocentric distances and contain a different mix of presolar components than Earth, they nevertheless are suitable proxies for Earth’s bulk chemical composition.

doi: 10.1038/nature18956

Primitive Solar System materials and Earth share a common initial 142Nd abundance p.399

The early evolution of planetesimals and planets can be constrained using variations in the abundance of neodymium-142 (142Nd), which arise from the initial distribution of 142Nd within the protoplanetary disk and the radioactive decay of the short-lived samarium-146 isotope (146Sm). The apparent offset in 142Nd abundance found previously between chondritic meteorites and Earth has been interpreted either as a possible consequence of nucleosynthetic variations within the protoplanetary disk or as a function of the differentiation of Earth very early in its history. Here we report high-precision Sm and Nd stable and radiogenic isotopic compositions of four calcium–aluminium-rich refractory inclusions (CAIs) from three CV-type carbonaceous chondrites, and of three whole-rock samples of unequilibrated enstatite chondrites. The CAIs, which are the first solids formed by condensation from the nebular gas, provide the best constraints for the isotopic evolution of the early Solar System. Using the mineral isochron method for individual CAIs, we find that CAIs without isotopic anomalies in Nd compared to the terrestrial composition share a 146Sm/144Sm–142Nd/144Nd isotopic evolution with Earth. The average 142Nd/144Nd composition for pristine enstatite chondrites that we calculate coincides with that of the accessible silicate layers of Earth. This relationship between CAIs, enstatite chondrites and Earth can only be a result of Earth having inherited the same initial abundance of 142Nd and chondritic proportions of Sm and Nd. Consequently, 142Nd isotopic heterogeneities found in other CAIs and among chondrite groups may arise from extrasolar grains that were present in the disk and incorporated in different proportions into these planetary objects. Our finding supports a chondritic Sm/Nd ratio for the bulk silicate Earth and, as a consequence, chondritic abundances for other refractory elements. It also removes the need for a hidden reservoir or for collisional erosion scenarios to explain the 142Nd/144Nd composition of Earth.

doi: 10.1038/nature19351

Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection p.412

During chronic viral infection, virus-specific CD8+ T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8+ T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8+ T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5+ CD8+ T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5+ subset. Furthermore, we identified the Id2–E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5+ CD8+ T-cell subset, and its number was inversely correlated with viral load. The CXCR5+ subset showed greater therapeutic potential than the CXCR5+ subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8+ T cells that has a pivotal role in the control of viral replication during chronic viral infection.

doi: 10.1038/nature19317

Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy p.417

Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

doi: 10.1038/nature19330

A PGC1α-mediated transcriptional axis suppresses melanoma metastasis p.422

Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis. Although metabolic reprogramming is tightly associated with tumour progression, the effect of metabolic regulatory circuits on metastatic processes is poorly understood. PGC1α is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms melanoma metabolism to influence drug sensitivity and survival. Here, we provide data indicating that PGC1α suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1α expression inversely correlates with vertical growth in human melanoma specimens. PGC1α silencing makes poorly metastatic melanoma cells highly invasive and, conversely, PGC1α reconstitution suppresses metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1α levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1α directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 causes downregulation of metastasis-related genes, including integrins that are known to influence invasion and metastasis. Inhibition of BRAFV600E using vemurafenib, independently of its cytostatic effects, suppresses metastasis by acting on the PGC1α–ID2–TCF4–integrin axis. Together, our findings reveal that PGC1α maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel acting transcriptional programs. Consequently, components of these circuits define new therapeutic opportunities that may help to curb melanoma metastasis.

doi: 10.1038/nature19347