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.
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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