Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD-1+ CD44highCD4+ T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1+ CD44highCD4+ T cells develop as unique T follicular (TF) cells in a B cell–dependent manner and consist of two subpopulations, as follows: CD153+ cells preferentially secreting abundant osteopontin on TCR stimulation and CD153− cells that are apparently TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the spontaneous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4+ T cell proliferation in vivo, suggesting replicative senescence. Although the CD153+ TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor–induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153+ PD-1+ CD4+ T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153+ TF cells generated as a consequence of extensive endogenous CD4+ T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmunity risk with age.

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Inhibitory effects of docosahexaenoic acid (DHA) on blood vessel contractions induced by various constrictor stimulants were investigated in the rat thoracic aorta. The inhibitory effects of DHA were also compared with those of eicosapentaenoic acid (EPA) and linoleic acid (LA). DHA exhibited a strong inhibitory effect on the sustained contractions induced by U46619, a TXA2 mimetic. This inhibitory effect of DHA was not affected by removal of the endothelium or by treatment with either indomethacin or Nω-nitro-l-arginine. DHA also significantly diminished PGF2α-induced contraction but did not show any appreciable inhibitory effects on the contractions to both phenylephrine (PE) and high-KCl. Similarly, EPA exhibited significant inhibitory effects against the contractions induced by both U46619 and PGF2α without substantially affecting either PE- or high-KCl-induced contractions. However, both DHA and EPA generated more potent inhibitions against contractions induced by U46619 than those by PGF2α. In contrast, LA did not show significant inhibitory effects against any contractions, including those induced by U46619. The present findings suggest that DHA and EPA elicit more selective inhibition against blood vessel contractions that are mediated through stimulation of prostanoid receptors than those through α-adrenoceptor stimulation or membrane depolarization. Although DHA and EPA have similar inhibitory potencies against prostanoid receptor-mediated contractions, they had a more potent inhibition against TXA2 receptor (TP receptor)-mediated contractions than against PGF2α receptor (FP receptor)-mediated responses. Selective inhibition by either DHA or EPA of prostanoid receptor-mediated blood vessel contractions may partly underlie the mechanisms by which these ω-3 polyunsaturated fatty acids exert their circulatory-protective effects.

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SYNOPSISN-Phenylmaleimide (PMI) -N-cyclohexylmaleimide (CMI) -styrene (St) terpolymers were used to improve the toughness of bisphenol-A diglycidyl ether epoxy resin cured with p,p'diaminodiphenyl sulfone (DDS) . The terpolymers were effective as modifiers for toughening of the epoxy resin system. The most suitable compositions for the modification of the epoxy resin were inclusion of 10 wt % of the terpolymer (45 mol % PMI, 5 mol % CMI, and 50 mol % St units) with M , higher than 247,000, which led to ca. a 140% increase in the fracture toughness (&) of the cured resin with a medium expense of mechanical properties. The glass transition temperatures of the modified resins were equal to or higher than that of the parent epoxy resin. The morphologies of the modified resins were dependent on the terpolymer molecular weight and concentration. On addition of 5 wt % of the terpolymer ( M , 400,000), the modified resins had two-phase morphologies and the terpolymer-rich dispersed particles in the epoxy matrix. On addition of more than 8 wt % of the terpolymer, the morphologies of the cured resins changed drastically and showed a tendency to form cocontinuous phases. The toughening mechanism was discussed in terms of the morphological behaviors of the modified epoxy resin systems.

Immune aging may underlie various aging-related disorders, including diminished resistance to infection, chronic inflammatory disorders, and autoimmunity. PD-1+ and CD153+ CD44high CD4+ T cells with features of cellular senescence, termed senescence-associated T (SA-T) cells, increasingly accumulate with age and may play a role in the immune aging phenotype. In this article, we demonstrate that, compared with young mice, the aged mouse environment is highly permissive for spontaneous proliferation of transferred naive CD4+ T cells, and it drives their transition to PD-1+ and CD153+ CD44high CD4+ T cells after extensive cell divisions. CD4+ T cells with essentially the same features as SA-T cells in aged mice are also generated from naive CD4+ T cells after extensive cell divisions under severe T-lymphopenic conditions by gamma irradiation or in developmental T cell defect, often in association with spontaneous germinal centers, as seen in aged mice. The increase in SA-T cells is significantly enhanced after thymectomy at the young adult stage, along with accelerated T cell homeostatic proliferation, whereas embryonic thymus implantation in the late adult stage markedly restricts the homeostatic proliferation of naive CD4+ T cells in the host and delays the increase in SA-T cells. Our results suggest that reduced T cell output due to physiologic thymic involution underlies the age-dependent accumulation of SA-T cells as a result of increasing homeostatic proliferation of naive CD4+ T cells. SA-T cells may provide a suitable biomarker of immune aging, as well as a potential target for controlling aging-related disorders.

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