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 receptor1–4. 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 naïve 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.

Initiated by excited-state intramolecular proton transfer (ESIPT) reaction, an overall reaction cycle of 4-(2-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H)-one (o-HBDI), an analogue of the core chromophore of the green fluorescent protein (GFP), has been investigated. In contrast to the native GFP core, 4-(4-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H)-one (p-HBDI), which requires hydrogen-bonding relay to accomplish proton transfer in vivo, o-HBDI possesses a seven-membered-ring intramolecular hydrogen bond and thus provides an ideal system for mimicking an intrinsic proton-transfer reaction. Upon excitation, ESIPT takes place in o-HBDI, resulting in a ∼600 nm proton-transfer tautomer emission. The o-HBDI tautomer emission, resolved by fluorescence upconversion, is comprised of an instantaneous rise to a few hundred femtosecond oscillation in the early relaxation stage. Frequency analysis derived from ultrashort pulse gives two low-frequency vibrations at 115 and 236 cm(-1), corresponding to skeletal deformation motions associated with the hydrogen bond. The results further conclude that ESIPT in o-HBDI is essentially triggered by low-frequency motions and may be barrierless along the reaction coordinate. Femtosecond UV/vis transient absorption spectra also provide supplementary evidence for the structural evolution during the reaction. In CH(3)CN, an instant rise of a 530 nm transient is resolved, which then undergoes 7.8 ps decay, accompanied by the growth of a rather long-lived 580 nm transient species. It is thus concluded that following ESIPT the cis-proton transfer isomer undergoes cis-trans-isomerization. The results of viscosity-dependent dynamics are in favor of the one-bond-flip mechanism, which is in contrast to the volume-conserving isomerization behavior for cis-stilbene and p-HBDI. Further confirmation is given by the picosecond-femtosecond transient IR absorption spectra, where several new and long-lived IR bands in the range of 1400-1500 cm(-1) are assigned to the phenyl in-plane breathing motions of the trans-proton transfer tautomer. Monitored by the nanosecond transient absorption, the 580 nm transient undergoes a ∼7.7 μs decay constant, accompanied by the growth of a new ∼500 nm band. The latter is assigned to a deprotonated tautomer species, which then undergoes the ground-state reverse proton recombination to the original o-HBDI in ∼50 μs, achieving an overall, reversible proton transfer cycle. This assignment is unambiguously supported by pump-probe laser induced fluorescence studies. On these standpoints, a comparison of photophysical properties among o-HBDI, p-HBDI, and wild-type GFP is discussed in detail.

Proton transfer is one of the most important elementary reactions in chemistry and biology. The role of proton in the course of proton transfer, whether it is active or passive, has been the subject of intense investigations. Here we demonstrate the active role of proton in the excited state intramolecular proton transfer (ESIPT) of 10-hydroxybenzo[h]quinoline (HBQ). The ESIPT of HBQ proceeds in 12 ± 6 fs, and the rate is slowed down to 25 ± 5 fs for DBQ where the reactive hydrogen is replaced by deuterium. The results are consistent with the ballistic proton wave packet transfer within the experimental uncertainty. This ultrafast proton transfer leads to the coherent excitation of the vibrational modes of the product state. In contrast, ESIPT of 2-(2'-hydroxyphenyl)benzothiazole (HBT) is much slower at 62 fs and shows no isotope dependence implying complete passive role of the proton.

The ultrafine-grained Ni-enriched Li[Ni0.95Co0.04Mo0.01]O2 (NCMo95) cathode achieved by inhibiting particle coarsening imparts the necessary mechanical toughness and significantly extends the battery life.

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T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. Recently, antibodies blocking PD-1 have been approved for use in cancer patients. In this review, we summarize the role of the PD-1 pathway in chronic infection and cancer and the therapeutic potential of PD-1-directed immunotherapy in patients with chronic infection or cancer.

SUMMARY T cell dysfunction is well documented during chronic viral infections but little is known about functional abnormalities in humoral immunity. Here we report that mice chronically infected with lymphocytic choriomeningitis virus (LCMV) exhibit a severe defect in Fcγ-receptor (FcγR)-mediated antibody effector functions. Using transgenic mice expressing human CD20 we found that chronic LCMV infection impaired the depletion of B cells with rituximab, an anti-CD20 antibody widely used for the treatment of B cell lymphomas. In addition, FcγR-dependent activation of dendritic cells by agonistic anti-CD40 antibody was compromised in chronically infected mice. These defects were due to viral antigen-antibody complexes and not the chronic infection per se, since FcγR-mediated effector functions were normal in chronically infected mice that lacked LCMV-specific antibodies. Our findings have implications for the therapeutic use of antibodies to treat cancer, autoimmunity and infectious diseases and suggest that pre-existing immune complexes could limit the effectiveness of antibody therapy.

Kikuchi-Fujimoto disease (KFD) is a benign, self-limiting disease characterized by cervical lymphadenopathy. Although it was primarily thought to be a disease of young adults, it has been increasingly recognized in children. To define the characteristics of KFD in children, we reviewed the medical records of patients younger than 18 years of age who were diagnosed with KFD from 2001 to 2012 at Korea University Medical Center, as well as worldwide published reports of KFD. A total of 140 pediatric patients and 733 patients of all ages was analyzed. Compared to the female predominance found in adults (2:1), young boys were more commonly affected than young girls (1.4:1). Cervical lymphadenopathy was the most common clinical finding in children, as it was in adults. Lymphadenopathy was more likely to be tender (69 vs. 44 %, p < 0.001) but less generalized (1 vs. 8 %, p < 0.05) in children compared to adults. Fever (82 vs. 35 %, p < 0.001) and rash (10 vs. 4 %, p < 0.05) were observed in children more commonly than in adults. Leukopenia was observed in 50 and 38 % of children and adults, respectively. Rates of recurrence and association with autoimmune diseases in children were comparable to those of adults. Cervical lymphadenopathy was the most common clinical manifestation of KFD in all ages. While fever and rash were more common in children with KFD compared to adults, generalized lymphadenopathy was rarer.