Dysfunction of type 1 and type 2 immune cells: a lesson from exhausted-like ILC2s and their activation-induced cell death.

The concept of immune cell exhaustion/dysfunction has developed mainly to understand impaired type 1 immune responses especially by CD8 T cells against tumors or virus-infected cells and has been applied to other lymphocytes. Natural killer (NK) cells and CD4 T cells support the efficient activation of CD8 T cells but exhibit a dysfunctional phenotype in tumor microenvironments and in chronic virus infections. In contrast, the concept of type 2 immune cell exhaustion/dysfunction is poorly established. Group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells are the major lymphocyte subsets that initiate and expand type 2 immune responses for antiparasitic immunity or allergy. In mouse models of chronic parasitic worm infections, Th2 cells display impaired type 2 immune responses. Chronic airway allergy induces exhausted-like ILC2s that quickly fall into activation-induced cell death to suppress exaggerated inflammation. Thus, the modes of exhaustion/dysfunction are quite diverse and rely on the types of inflammation and the cells. In this review, we summarize current knowledge of lymphocyte exhaustion/dysfunction in the context of type 1 and type 2 immune responses and discuss ILC2-specific regulatory mechanisms during chronic allergy.

Comparison of the prognostic impact of IPI and PIT in peripheral T-cell lymphoma in real-world practice with a large elderly population.

We compared the predictive ability of the International Prognostic Index (IPI), a frequently used prognostic model for peripheral T-cell lymphoma (PTCL), with that of a type-specific prognostic model, the Prognostic Index for PTCL-U (PIT). We retrospectively analyzed 113 patients diagnosed with PTCL. The median age was 67 years (range, 16-88 years), 75 patients (66%) were male, and the most common disease type was PTCL, not otherwise specified (69%). With a median follow-up of 6.8 years (interquartile range, 2.7-9.9 years), 5-year survival rates for the four groups in IPI were 85%, 62%, 49%, and 13%, respectively. Similarly, 5-year survival rates for the four groups in PIT were 83%, 64%, 49%, and 19%, respectively. The area under the receiving operating characteristic curve for predicting mortality from PIT (0.725) was not significantly different from that from the IPI (0.685, P = 0.134). Multivariable analysis showed that performance status ≥ 2 (P < 0.0001) and extranodal lesions ≥ 2 (P = 0.029) were significantly associated with lower overall survival. The present study found no significant difference in prognostic ability between the IPI and PIT for PTCL, and both models appear useful as predictive models.

D-band optical modulators using electro-optic polymer waveguides and non-coplanar patch antennas.

D-band (110-170 GHz) antenna-coupled optical modulators with electro-optic (EO) polymer waveguides and non-coplanar patch antennas were fabricated using a poled EO polymer film transfer method. A carrier-to-sideband ratio (CSR) of 42.3 dB corresponding to an optical phase shift of 15.3 mrad was obtained by irradiating 150 GHz electromagnetic waves with an irradiation power density of 34.3 W/m2. Our devices and fabrication method have great potential for achieving highly efficient wireless-to-optical signal conversion in radio-over-fiber (RoF) systems.

TIGIT mediates activation-induced cell death of ILC2s during chronic airway allergy.

While group-2 innate lymphoid cells (ILC2s) are highly proliferative in allergic inflammation, the removal of overactivated ILC2s in allergic diseases has not been investigated. We previously showed that chronic airway allergy induces "exhausted-like" dysfunctional ILC2s expressing T cell immunoreceptor with Ig and ITIM domains (TIGIT). However, the physiological relevance of these cells in chronic allergy remains elusive. To precisely identify and monitor TIGIT+ ILC2s, we generated TIGIT lineage tracer mice. Chronic allergy stably induced TIGIT+ ILC2s, which were highly activated, apoptotic, and were quickly removed from sites of chronic allergy. Transcripts from coding genes were globally suppressed in the cells, possibly due to reduced chromatin accessibility. Cell death in TIGIT+ ILC2s was enhanced by interactions with CD155 expressed on macrophages, whereas genetic ablation of Tigit or blockade by anti-TIGIT antagonistic antibodies promoted ILC2 survival, thereby deteriorating chronic allergic inflammation. Our work demonstrates that TIGIT shifts the fate of ILC2s toward activation-induced cell death, which could present a new therapeutic target for chronic allergies.

Cryo-EM structures of an LRRC8 chimera with native functional properties reveal heptameric assembly.

Volume-regulated anion channels (VRACs) mediate volume regulatory Cl- and organic solute efflux from vertebrate cells. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown stoichiometries. Homomeric LRRC8A and LRRC8D channels have a small pore, hexameric structure. However, these channels are either non-functional or exhibit abnormal regulation and pharmacology, limiting their utility for structure-function analyses. We circumvented these limitations by developing novel homomeric LRRC8 chimeric channels with functional properties consistent with those of native VRAC/LRRC8 channels. We demonstrate here that the LRRC8C-LRRC8A(IL125) chimera comprising LRRC8C and 25 amino acids unique to the first intracellular loop (IL1) of LRRC8A has a heptameric structure like that of homologous pannexin channels. Unlike homomeric LRRC8A and LRRC8D channels, heptameric LRRC8C-LRRC8A(IL125) channels have a large-diameter pore similar to that estimated for native VRACs, exhibit normal DCPIB pharmacology, and have higher permeability to large organic anions. Lipid-like densities are located between LRRC8C-LRRC8A(IL125) subunits and occlude the channel pore. Our findings provide new insights into VRAC/LRRC8 channel structure and suggest that lipids may play important roles in channel gating and regulation.

Superiorly low half-wave voltage electro-optic polymer modulator for visible photonics.

Chip-scale optical devices operated at wavelengths shorter than communication wavelengths, such as LiDAR for autonomous driving, bio-sensing, and quantum computation, have been developed in the field of photonics. In data processing involving optical devices, modulators are indispensable for the conversion of electronic signals into optical signals. However, existing modulators have a high half-wave voltage-length product (VπL) which is not sufficient at wavelengths below 1000 nm. Herein, we developed a significantly efficient optical modulator which has low VπL of 0.52 V·cm at λ = 640 nm using an electro-optic (EO) polymer, with a high glass transition temperature (Tg = 164 °C) and low optical absorption loss (2.6 dB/cm) at λ = 640 nm. This modulator is not only more efficient than any EO-polymer modulator reported thus far, but can also enable ultra-high-speed data communication and light manipulation for optical platforms operating in the ranges of visible and below 1000 nm infrared.

Infrared and Terahertz Spectroscopic Investigation of Imidazolium, Pyridinium, and Tetraalkylammonium Tetrafluoroborate Ionic Liquids.

We performed terahertz time-domain spectroscopy and infrared spectroscopy of imidazolium-based, pyridinium-based, and tetraalkylammonium-based tetrafluoroborate ionic liquids to study their characteristic intermolecular and intramolecular vibrational modes to clarify interactions between various cations and the tetrafluoroborate anion. It was found that the central frequency of the intermolecular vibrational band for these ionic liquids has a relatively high frequency, ranging from 90 to 100 cm-1. In the 900-1150 cm-1 range, the intramolecular vibrational absorption band of the 3-fold degenerate mode of tetrafluoroborate anions in the ionic liquids was observed. Although the tetrafluoroborate anion is attributable to one of the weakly coordinated anions, the spectroscopic splitting behavior of the 3-fold degenerate mode differs depending on the cation species. It was revealed that the degenerate mode is very sensitive to local interactions between the tetrafluoroborate anion and each cation.

Prognostic impact of the controlling nutritional status score in patients with peripheral T-cell lymphoma.

The controlling nutritional status (CONUT) score is a simplified nutritional index calculated from serum albumin, total cholesterol, and total lymphocyte count. This study evaluated the prognostic impact of the CONUT score on overall survival (OS) in patients with peripheral T-cell lymphoma (PTCL). A multicenter, retrospective cohort study including 99 patients with PTCL was conducted. The CONUT score was significantly higher in the non-survivor group (median 5, range 0-12) than in the survivor group (median 3, range 0-11; p = 0.026). The CONUT score was an independent prognostic factor in a multivariable Cox proportional hazards model (hazard ratio 1.119, 95% confidence interval 1.021-1.227, p = 0.017). No significant effect-modification by the International Prognostic Index (IPI) was observed, and the CONUT score affected the prognosis of PTCL regardless of the IPI (P for interaction = 0.208). In conclusion, the CONUT score is an independent prognostic factor for PTCL irrespective of IPI category.

W-band optical modulators using electro-optic polymer waveguides and patch antenna arrays.

In this study, W-band (75-110 GHz) antenna-coupled optical modulators with a cyclo-olefin polymer (COP) lower cladding, an electro-optic (EO) polymer waveguide, and a gap-embedded patch antenna array were fabricated using a transfer and bonding method of a poled EO polymer film. A carrier-to-sideband ratio (CSR) of 56 dB corresponding to an optical phase shift of 3 mrad was obtained under irradiation with 100 GHz electromagnetic waves with a power of 12.8 W/m2. Our devices have the potential to achieve highly efficient wireless-optical signal conversion in radio-over-fiber (RoF) systems.

Infrared Spectroscopy in the Middle Frequency Range for Various Imidazolium Ionic Liquids-Common Spectroscopic Characteristics of Vibrational Modes with In-Plane +C(2)-H and +C(4,5)-H Bending Motions and Peak Splitting Behavior Due to Local Symmetry Breaking of Vibrational Modes of the Tetrafluoroborate Anion.

Various alkyl-methylimidazolium ionic liquids (ILs) were inspected using infrared spectroscopy in the middle frequency range. In the 1050-1200 cm-1 range, there is a skeletal vibrational mode accompanied with a large in-plane +C(2)-H bending motion and +C(4)-H and +C(5)-H motions, and in the 1500-1650 cm-1 range, there are two skeletal vibrational modes with in-plane +C(4,5)-H bending motions. Interestingly, in both ranges, we found that skeletal vibrational modes with a large in-plane +C(2)-H bending motion and in-plane +C(4,5)-H bending motions are insensitive to increases in the basicity of anions or the strengthening of hydrogen bond-type interactions, and the behaviors are completely different from those in the +C-H stretching vibrational modes in the 3000-3200 cm-1 range and the skeletal vibrational modes with large out-of-plane +C-H motions in the 700-950 cm-1 range. Furthermore, in alkyl-methylimidazolium tetrafluoroborate [C n mim+][BF4 -] ILs, we found that absorption due to the (threefold) degenerate vibrational mode of [BF4 -] was observed as a broad absorption band with three splitting peaks in the 900-1150 cm-1 range as a result of local symmetry breaking due to the cation-anion interactions.

Trained innate lymphoid cells in allergic diseases.

Group 2 innate lymphoid cells (ILC2s) reside in peripheral tissues such as the lungs, skin, nasal cavity, and gut and provoke innate type 2 immunity against allergen exposure, parasitic worm infection, and respiratory virus infection by producing TH2 cytokines. Recent advances in understanding ILC2 biology revealed that ILC2s can be trained by IL-33 or allergic inflammation, are long-lived, and mount memory-like type 2 immune responses to any other allergens afterwards. In contrast, IL-33, together with retinoic acid, induces IL-10-producing immunosuppressive ILC2s. In this review, we discuss how the allergic cytokine milieu and other immune cells direct the generation of trained ILC2s with immunostimulatory or immunosuppressive recall capability in allergic diseases and infections associated with type 2 immunity. The molecular mechanisms of trained immunity by ILCs and the physiological relevance of trained ILC2s are also discussed.

LRRC8A homohexameric channels poorly recapitulate VRAC regulation and pharmacology.

Swelling-activated volume-regulated anion channels (VRACs) are heteromeric channels comprising LRRC8A and at least one other LRRC8 paralog. Cryoelectron microscopy (cryo-EM) structures of nonnative LRRC8A and LRRC8D homohexamers have been described. We demonstrate here that LRRC8A homohexamers poorly recapitulate VRAC functional properties. Unlike VRACs, LRRC8A channels heterologously expressed in Lrr8c-/- HCT116 cells are poorly activated by low intracellular ionic strength (µ) and insensitive to cell swelling with normal µ. Combining low µ with swelling modestly activates LRRC8A, allowing characterization of pore properties. VRACs are strongly inhibited by 10 µM 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid (DCPIB) in a voltage-independent manner. In contrast, DCPIB block of LRRC8A is weak and voltage sensitive. Cryo-EM structures indicate that DCPIB block is dependent on arginine 103. Consistent with this, LRRC8A R103F mutants are insensitive to DCPIB. However, an LRRC8 chimeric channel in which R103 is replaced by a leucine at the homologous position is inhibited ∼90% by 10 µM DCPIB in a voltage-independent manner. Coexpression of LRRC8A and LRRC8C gives rise to channels with DCPIB sensitivity that is strongly µ dependent. At normal intracellular µ, LRRC8A + LRRC8C heteromers exhibit strong, voltage-independent DCPIB block that is insensitive to R103F. DCPIB inhibition is greatly reduced and exhibits voltage dependence with low intracellular µ. The R103F mutation has no effect on maximal DCPIB inhibition but eliminates voltage dependence under low µ conditions. Our findings demonstrate that the LRRC8A cryo-EM structure and the use of heterologously expressed LRRC8 heteromeric channels pose significant limitations for VRAC mutagenesis-based structure-function analysis. Native VRAC function is most closely mimicked by chimeric LRRC8 homomeric channels.

Efficacy of chemotherapy after progression with nivolumab in squamous cell carcinoma of the head and neck.

Nivolumab, a programmed death-1 (PD-1) inhibitor, has shown promising results against squamous cell carcinoma of the head and neck (SCCHN) in cases of recurrence or in a metastatic setting after platinum-based therapy. However, treatment alternatives for patients with nivolumab-refractory are limited, and a constant opinion is not provided. Recently, accumulating studies have demonstrated that chemotherapy after immune checkpoint inhibitor treatment may induce better objective responses in patients with advanced non-small cell lung cancer. However, there are few reports on the increased effect of chemotherapy after nivolumab treatment in SCCHN. Therefore, cases must be accumulated to identify patients with nivolumab-refractory SCCHN who may benefit from chemotherapy. Here, we present patients with SCCHN who exhibited a significant response to chemotherapy after nivolumab treatment.

Superior properties in room-temperature colloidal-dot quantum emitters revealed by ultralow-dark-count detections of temporally-purified single photons.

The realization of high-quality quantum emitters that can operate at room temperature is important for accelerating the application of quantum technologies, such as quantum communication, quantum information processing, and quantum metrology. In this work, we study the photon-antibunching properties on room-temperature emission from individual colloidal quantum dots (CQDs) using superconducting-nanowire single-photon detectors and temporal filtering of the photoluminescence decay curve. We find that high single-photon purities and high photon-generation rates can be simultaneously achieved by removing the signals originating from the sequential two-photon emission of biexcitons created by multiple excitation pulses. We successfully demonstrate that the ultrahigh performance of the room-temperature single-photon sources showing g(2)(0) ≪ 10-2 can be confirmed by the ultralow-dark-count detection of the temporally purified single photons. These findings provide strong evidence for the attractiveness of CQDs as candidates for high-quality room-temperature quantum light sources.

Follicular lymphoma suggested to transform into EBV-negative plasmablastic lymphoma.

Follicular lymphoma (FL) is an indolent lymphoma that often transforms into a high-grade lymphoma, mostly diffuse large B-cell lymphoma. A case of FL suggested to transform into plasmablastic lymphoma is presented. A 59-year-old man was admitted to our hospital because of right lower abdominal pain and vomiting. Computed tomography showed a mass in the ileocecum. Colonoscopy showed a mass with an ulcer in the ascending colon, and surgery was performed. Immunohistochemical staining of the biopsied mass showed infiltrated lymphocytes that were positive for CD38, CD45, CD138, and λ chain, and negative for CD4, CD5, CD8, CD10, CD20, CD56, and κ chain. Flow cytometric analysis of the ascites showed similar results. FISH analyses performed using lymph node biopsy specimens, ascite fluid and pleural effusion fluid identified the presence of an IGH/BCL2 translocation. FL was suggested to transform into PBL. Although the patient received three courses of R-CHOP chemotherapy and salvage chemotherapy, the patient died because of lymphoma progression less than 6 months after the diagnosis of PBL. Transformation of FL to PBL is highly unusual. The lack of a standard treatment for PBL results in the poor outcome of this entity. Novel therapeutic approaches are needed.

A 30-year journey from volume-regulated anion currents to molecular structure of the LRRC8 channel.

The swelling-activated anion channel VRAC has fascinated and frustrated physiologists since it was first described in 1988. Multiple laboratories have defined VRAC's biophysical properties and have shown that it plays a central role in cell volume regulation and possibly other fundamental physiological processes. However, confusion and intense controversy surrounding the channel's molecular identity greatly hindered progress in the field for >15 yr. A major breakthrough came in 2014 with the demonstration that VRAC is a heteromeric channel encoded by five members of the Lrrc8 gene family, Lrrc8A-E. A mere 4 yr later, four laboratories described cryo-EM structures of LRRC8A homomeric channels. As the melee of structure/function and physiology studies begins, it is critical that this work be framed by a clear understanding of VRAC biophysics, regulation, and cellular physiology as well as by the field's past confusion and controversies. That understanding is essential for the design and interpretation of structure/function studies, studies of VRAC physiology, and studies aimed at addressing the vexing problem of how the channel detects cell volume changes. In this review we discuss key aspects of VRAC biophysics, regulation, and function and integrate these into our emerging understanding of LRRC8 protein structure/function.

Terahertz-wave generation devices using electro-optic polymer slab waveguides and cyclo-olefin polymer clads.

We fabricated terahertz (THz) wave generation devices using electro-optic (EO) polymer slab waveguides and cyclo-olefin polymer (COP) clads with very small absorption loss of the THz waves based on a novel device fabrication procedure involving bonding of the poled EO polymer layer to the COP substrates. We demonstrated THz wave generation from the EO polymer slab devices using a 1.55 µm-band femtosecond fiber laser and evaluated the THz wave generation properties of the devices. Our results will lead to the development of compact, highly efficient, and ultrabroadband THz devices using EO polymers.

R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial.

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R-THP-COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R-THP-COP and standard R-CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R-CHOP group, 40 patients; R-THP-COP group, 41 patients). R-THP-COP was noninferior to R-CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow-up of 75.2 months, the 5-year overall survival was 87% in the R-CHOP group and 82% in the R-THP-COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31-2.49; P = .82). The 5-year progression-free survival was 74% in the R-CHOP group and 79% in the R-THP-COP group (HR: 1.37, 95% CI: 0.56-3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy-related acute myeloid leukemia in the R-THP-COP group. These data indicate that R-THP-COP is noninferior to R-CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R-CHOP.

Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function.

The volume-regulated anion channel (VRAC) is expressed ubiquitously in vertebrate cells and mediates swelling-induced release of Cl- and organic solutes. Recent studies by several laboratories have demonstrated conclusively that VRAC is encoded by members of the leucine-rich repeat containing 8 (Lrrc8) gene family, which comprises five members, termed Lrrc8a-e. Numerous observations indicate that VRAC is a heteromeric channel comprising the essential subunit LRRC8A and one or more of the other LRRC8 paralogs. Here we demonstrate that the intracellular loop (IL) connecting transmembrane domains 2 and 3 of LRRC8A and the first extracellular loop (EL1) connecting transmembrane domains 1 and 2 of LRRC8C, LRRC8D, or LRRC8E are both essential for VRAC activity. We generate homomeric VRACs by replacing EL1 of LRRC8A with that of LRRC8C and demonstrate normal regulation by cell swelling and shrinkage. We also observe normal volume-dependent regulation in VRAC homomers in which the IL of LRRC8C, LRRC8D, or LRRC8E is replaced with the LRRC8A IL. A 25-amino acid sequence unique to the LRRC8A IL is sufficient to generate homomeric VRAC activity when inserted into the corresponding region of LRRC8C and LRRC8E. LRRC8 chimeras containing these partial LRRC8A IL sequences exhibit altered anion permeability, rectification, and voltage sensitivity, suggesting that the LRRC8A IL plays a role in VRAC pore structure and function. Our studies provide important new insights into the structure/function roles of the LRRC8 EL1 and IL. Homomeric LRRC8 channels will simplify future studies aimed at understanding channel structure and the longstanding and vexing problem of how VRAC is regulated by cell volume changes.