Physiology and pathology of T-cell aging

Acquired immune function shows recognizable changes over time with organismal aging. These changes include T-cell dysfunction, which may underlie diminished resistance to infection and possibly various chronic age-associated diseases in the elderly. T-cell dysfunction may occur at distinct stages, from naive cells to the end stages of differentiation during immune responses. The thymus, which generates naive T cells, shows unusually early involution resulting in progressive reduction of T-cell output after adolescence, but peripheral T-cell numbers are maintained through antigen-independent homeostatic proliferation of naive T cells driven by the major histocompatibility complex associated with self-peptides and homeostatic cytokines, retaining the diverse repertoire. However, extensive homeostatic proliferation may lead to the emergence of dysfunctional CD4+ T cells with features resembling senescent cells, termed senescence-associated T (SA-T) cells, which increase and accumulate with age. In situations such as chronic viral infection, T-cell dysfunction may also develop via persistent antigen stimulation, termed exhaustion, preventing possible immunopathology due to excessive immune responses. Exhausted T cells are developed through the effects of checkpoint receptors such as PD-1 and may be reversed with the receptor blockade. Of note, although defective in their regular T-cell antigen-receptor-mediated proliferation, SA-T cells secrete abundant pro-inflammatory factors such as osteopontin, reminiscent of an SA-secretory phenotype. A series of experiments in mouse models indicated that SA-T cells are involved in systemic autoimmunity as well as chronic tissue inflammation following tissue stresses. In this review, we discuss the physiological aspects of T-cell dysfunction associated with aging and its potential pathological involvement in age-associated diseases and possibly cancer

cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells

老化T細胞が自己免疫病や慢性炎症疾患を引き起こすメカニズムを解明 --老化関連疾患克服への新しいアプローチ--. 京都大学プレスリリース. 2022-09-22.With age, senescence-associated (SA) CD4+ T cells that are refractory to T cell receptor (TCR) stimulation are increased along with spontaneous germinal center (Spt-GC) development prone to autoantibody production. We demonstrate that CD153 and its receptor CD30 are expressed in SA-T and Spt-GC B cells, respectively, and deficiency of either CD153 or CD30 results in the compromised increase of both cell types. CD153 engagement on SA-T cells upon TCR stimulation causes association of CD153 with the TCR/CD3 complex and restores TCR signaling, whereas CD30 engagement on GC B cells induces their expansion. Administration of an anti-CD153 antibody blocking the interaction with CD30 suppresses the increase in both SA-T and Spt-GC B cells with age and ameliorates lupus in lupus-prone mice. These results suggest that the molecular interaction of CD153 and CD30 plays a central role in the reciprocal activation of SA-T and Spt-GC B cells, leading to immunosenescent phenotypes and autoimmunity

Synthesis of carbon nanotubes by microwave heating: Influence of diameter of catalytic Ni nanoparticles on diameter of CNTs

We rapidly synthesized multi walled carbon nanotubes (MWCNTs) by calcination of granulated polystyrene with nickel nanoparticles having different average diameter (D-Ni = 10, 20, 50 or 90 nm) under nitrogen gas at a certain temperature and time (700 degrees C, 15 min or 800 degrees C, 10 min), using a domestic microwave oven in order to systematically investigate the influence of the diameter of nickel nanoparticles on the diameter of MWCNTs. The MWCNTs synthesized here were characterized by a transmission electron microscope, a Raman spectrophotometer and a wide angle X-ray diffractometer. We found that for the calcination condition of (800 degrees C, 10 min), a relationship between the outer diameter of the resulted carbon nanotubes (D-CNT) and the diameter of catalytic nickel nanoparticles (D-Ni) can be described as a linear function, D-CNT = 1.01D(Ni) + 14.79 nm with the correlation coefficient R = 0.99, and that for the calcination condition of 700 degrees C, 15 min, D-CNT = 1.12D(Ni) + 7.80 nm with R = 0.95. Thus, we revealed that when the diameter of the catalytic nickel nanoparticles (D-Ni) increases by 1 nm, the outer diameter of the obtained MWCNTs (D-CNT) increases by about 1 nm.ArticleJOURNAL OF MATERIALS CHEMISTRY A. 2(8):2773-2780 (2014)journal articl

Photoinduced swing of a diarylethene thin broad sword shaped crystal:a study on the detailed mechanism

We report a swinging motion of photochromic thin broad sword shaped crystals upon continuous irradiation with UV light. By contrast in thick crystals, photosalient phenomena were observed. The bending and swinging mechanisms are in fact due to molecular size changes as well as phase transitions. The first slight bending away from the light source is due to photocyclization-induced surface expansion, and the second dramatic bending toward UV incidence is due to single-crystal-to-single-crystal (SCSC) phase transition from the original phase I to phase IIUV. Upon visible light irradiation, the crystal returned to phase I. A similar SCSC phase transition with a similar volume decrease occurred by lowering the temperature (phase IIItemp). For both photoinduced and thermal SCSC phase transitions, the symmetry of the unit cell is lowered; in phase IIUV the twisting angle of disordered phenyl groups is different between two adjacent molecules, while in phase IIItemp, the population of the phenyl rotamer is different between adjacent molecules. In the case of phase IIUV, we found thickness dependent photosalient phenomena. The thin broad sword shaped crystals with a 3 mu m thickness showed no photosalient phenomena, whereas photoinduced SCSC phase transition occurred. In contrast, large crystals of several tens of mu m thickness showed photosalient phenomena on the irradiated surface where SCSC phase transition occurred. The results indicated that the accumulated strain, between isomerized and non-isomerized layers, gave rise to the photosalient phenomenon

Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor

IntroductionImmune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. MethodsWe investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).ResultsThe genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs.DiscussionOur Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

高齢者腎臓病を悪化させる原因細胞・分子の同定に成功. 京都大学プレスリリース. 2021-11-30.A new drug target for kidney disease. 京都大学プレスリリース. 2021-11-30.Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153⁺PD-1⁺CD4⁺ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL21 and IFNγ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153-CD30 signaling in TLT formation and propose targeting CD153-CD30 signaling pathway as a therapeutic target for slowing kidney disease progression

Lyman Alpha Emitters at z=7 in the Subaru/XMM-Newton Deep Survey Field: Photometric Candidates and Luminosity Function

We conducted a deep narrowband NB973 (FWHM = 200 A centered at 9755 A) survey of z=7 Lyman alpha emitters (LAEs) in the Subaru/XMM-Newton Deep Survey Field, using the fully depleted CCDs newly installed on the Subaru Telescope Suprime-Cam, which is twice more sensitive to z=7 Lyman alpha at ~ 1 micron than the previous CCDs. Reaching the depth 0.5 magnitude deeper than our previous survey in the Subaru Deep Field that led to the discovery of a z=6.96 LAE, we detected three probable z=7 LAE candidates. Even if all the candidates are real, the Lyman alpha luminosity function (LF) at z=7 shows a significant deficit from the LF at z=5.7 determined by previous surveys. The LAE number and Lyman alpha luminosity densities at z=7 is ~ 7.7-54% and ~5.5-39% of those at z=5.7 to the Lyman alpha line luminosity limit of L(Ly-alpha) >~ 9.2 x 10^{42} erg s^{-1}. This could be due to evolution of the LAE population at these epochs as a recent galaxy evolution model predicts that the LAE modestly evolves from z=5.7 to 7. However, even after correcting for this effect of galaxy evolution on the decrease in LAE number density, the z=7 Lyman alpha LF still shows a deficit from z=5.7 LF. This might reflect the attenuation of Lyman alpha emission by neutral hydrogen remaining at the epoch of reionization and suggests that reionization of the universe might not be complete yet at z=7. If we attribute the density deficit to reionization, the intergalactic medium (IGM) transmission for Lyman alpha photons at z=7 would be 0.4 <= T_{Ly-alpha}^{IGM} <= 1, supporting the possible higher neutral fraction at the earlier epochs at z > 6 suggested by the previous surveys of z=5.7-7 LAEs, z ~ 6 quasars and z > 6 gamma-ray bursts.Comment: Accepted to ApJ for publicatio

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

石川県立中央病院金沢大学医薬保健研究域医学系Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes. Methods We measured serum iron parameters and hepcidin- 25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE hemochromatosis. Results One patient with HJV hemochromatosis, 2 with TFR2 hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. Conclusion Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis. © Springer 2010