Donor colonic CD103(+) dendritic cells determine the severity of acute graft-versus-host disease

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.Motoko Koyama, Melody Cheong, Kate A. Markey, Kate H. Gartlan, Rachel D. Kuns, Kelly R. Locke, Katie E. Lineburg, Bianca E. Teal, Lucie Leveque-El mouttie, Mark D. Bunting, Slavica Vuckovic, Ping Zhang, Michele W.L. Teng, Antiopi Varelias, Siok-Keen Tey, Leesa F. Wockner, Christian R. Engwerda, Mark J. Smyth, Gabrielle T. Belz, Shaun R. McColl, Kelli P.A. MacDonald, and Geoffrey R. Hil

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation.

FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation

Search for lensing signatures in the gravitational-wave observations from the first half of LIGO-Virgo's third observing run

We search for signatures of gravitational lensing in the gravitational-wave signals from compact binary coalescences detected by Advanced LIGO and Advanced Virgo during O3a, the first half of their third observing run. We study: 1) the expected rate of lensing at current detector sensitivity and the implications of a non-observation of strong lensing or a stochastic gravitational-wave background on the merger-rate density at high redshift; 2) how the interpretation of individual high-mass events would change if they were found to be lensed; 3) the possibility of multiple images due to strong lensing by galaxies or galaxy clusters; and 4) possible wave-optics effects due to point-mass microlenses. Several pairs of signals in the multiple-image analysis show similar parameters and, in this sense, are nominally consistent with the strong lensing hypothesis. However, taking into account population priors, selection effects, and the prior odds against lensing, these events do not provide sufficient evidence for lensing. Overall, we find no compelling evidence for lensing in the observed gravitational-wave signals from any of these analyses

Search for Lensing Signatures in the Gravitational-Wave Observations from the First Half of LIGO-Virgo's Third Observing Run

We search for signatures of gravitational lensing in the gravitational-wave signals from compact binary coalescences detected by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) and Advanced Virgo during O3a, the first half of their third observing run. We study: (1) the expected rate of lensing at current detector sensitivity and the implications of a non-observation of strong lensing or a stochastic gravitational-wave background on the merger-rate density at high redshift; (2) how the interpretation of individual high-mass events would change if they were found to be lensed; (3) the possibility of multiple images due to strong lensing by galaxies or galaxy clusters; and (4) possible wave-optics effects due to point-mass microlenses. Several pairs of signals in the multiple-image analysis show similar parameters and, in this sense, are nominally consistent with the strong lensing hypothesis. However, taking into account population priors, selection effects, and the prior odds against lensing, these events do not provide sufficient evidence for lensing. Overall, we find no compelling evidence for lensing in the observed gravitational-wave signals from any of these analyses

Model-based Cross-correlation Search for Gravitational Waves from the Low-mass X-Ray Binary Scorpius X-1 in LIGO O3 Data

We present the results of a model-based search for continuous gravitational waves from the low-mass X-ray binary Scorpius X-1 using LIGO detector data from the third observing run of Advanced LIGO and Advanced Virgo. This is a semicoherent search that uses details of the signal model to coherently combine data separated by less than a specified coherence time, which can be adjusted to balance sensitivity with computing cost. The search covered a range of gravitational-wave frequencies from 25 to 1600 Hz, as well as ranges in orbital speed, frequency, and phase determined from observational constraints. No significant detection candidates were found, and upper limits were set as a function of frequency. The most stringent limits, between 100 and 200 Hz, correspond to an amplitude h0 of about 10−25 when marginalized isotropically over the unknown inclination angle of the neutron star's rotation axis, or less than 4 × 10−26 assuming the optimal orientation. The sensitivity of this search is now probing amplitudes predicted by models of torque balance equilibrium. For the usual conservative model assuming accretion at the surface of the neutron star, our isotropically marginalized upper limits are close to the predicted amplitude from about 70 to 100 Hz; the limits assuming that the neutron star spin is aligned with the most likely orbital angular momentum are below the conservative torque balance predictions from 40 to 200 Hz. Assuming a broader range of accretion models, our direct limits on gravitational-wave amplitude delve into the relevant parameter space over a wide range of frequencies, to 500 Hz or more