CD4 and CD8 T cells require different membrane gangliosides for activation

Nagafuku, Masakazu; Okuyama, Kaori; Onimaru, Yuri; Suzuki, Akemi; Odagiri, Yuta; Yamashita, Tadashi; Iwasaki, Katsunori; Fujiwara, Michihiro; Takayanagi, Motowo; Ohno, Isao; Inokuchi, Jin-ichi

doi:10.1073/pnas.1114965109

Cited by 119 publications

(98 citation statements)

References 48 publications

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“…The essential proximal TCR signaling molecules LCK and LAT reside in different lipid raft subsets that fuse upon TCR stimulation (33), and the interaction of TCR-associated signaling molecules (including LCK, LFA1, and PI3K) with GM3 or GM1 induces differential recruitment of downstream signaling targets that affect T cell function (34,35). Moreover, recent reports show that CD4 + and CD8 + T cells exclusively require a-series and o-series GSLs, respectively, for TCR-mediated activation (8,36). The reduction of cellular GSL levels by pharmacological means or by disruption of GM3 synthase activity can inhibit the differentiation of CD4 + T cells into Th17 cells (7) and reduce cytokine production in activated T cells during viral infection (31).…”

Section: Discussionmentioning

confidence: 99%

“…GSLs are enriched predominantly in lipid rafts, regions in the plasma membrane that coordinate the interaction of key signaling molecules that facilitate lymphocyte activation and function (2,5). Furthermore, differential GSL expression influences a range of T cell functions including TCR-mediated signaling (6)(7)(8), apoptosis (9), and recycling and endocytosis of membrane signaling and receptor molecules (4).…”

Section: Introductionmentioning

confidence: 99%

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Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

McDonald¹,

Deepak²,

Miguel³

et al. 2014

J. Clin. Invest.

137

120

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Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4 + T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4 + T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4 + T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4 + T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

McDonald¹,

Deepak²,

Miguel³

et al. 2014

J. Clin. Invest.

137

120

View full text Add to dashboard Cite

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“…3). CTB shows high affinity and specificity for GM1, recognizing the I 3 -sialosylgangliotriaose moiety, Gal␤1,3GalNAc␤1,4(Sia␣2,3) Gal␤1 (43,44). In preliminary studies, Wa infectivity was inhibited to the same extent (48% Ϯ 3%) by CTB at 10 g/ml as at 1 g/ml (Fig.…”

Section: Resultsmentioning

confidence: 82%

“…Although reduced by cellular CTB treatment, Wa infectivity in untreated cells is not inhibited by Neu5Ac␣2Me. This may be because Neu5Ac␣2Me can only compete with VP8* binding to GM1 via the internal Sia, whereas CTB has an extensive a-GM1 binding footprint [the I 3 -sialosylgangliotriaose moiety, Gal␤1,3GalNAc␤1,4(Sia␣2,3)Gal␤1], and high (sub-M) GM1 affinity (43,44). The possibility also exists that Wa preferentially uses alternative receptors on untreated cells, such as the ␣2␤1 integrin, in a manner that is unaffected by Neu5Ac␣2Me competition.…”

mentioning

confidence: 99%

Relative Roles of GM1 Ganglioside, N -Acylneuraminic Acids, and α2β1 Integrin in Mediating Rotavirus Infection

Fleming

Böhm

Dang

et al. 2014

J Virol

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N-acetyl-and N-glycolylneuraminic acids (Sia) and ␣2␤1 integrin are frequently used by rotaviruses as cellular receptors through recognition by virion spike protein VP4. The VP4 subunit VP8*, derived from Wa rotavirus, binds the internal N-acetylneuraminic acid on ganglioside GM1. Wa infection is increased by enhanced internal Sia access following terminal Sia removal from main glycan chains with sialidase. The GM1 ligand cholera toxin B (CTB) reduces Wa infectivity. Here, we found sialidase treatment increased cellular GM1 availability and the infectivity of several other human (including RV-3) and animal rotaviruses, typically rendering them susceptible to methyl ␣-D-N-acetylneuraminide treatment, but did not alter ␣2␤1 usage. CTB reduced the infectivity of these viruses. Aceramido-GM1 inhibited Wa and RV-3 infectivity in untreated and sialidasetreated cells, and GM1 supplementation increased their infectivity, demonstrating the importance of GM1 for infection. Wa recognition of ␣2␤1 and internal Sia were at least partially independent. Rotavirus usage of GM1 was mapped to VP4 using virus reassortants, and RV-3 VP8* bound aceramido-GM1 by saturation transfer difference nuclear magnetic resonance (STD NMR). Most rotaviruses recognizing terminal Sia did not use GM1, including RRV. RRV VP8* interacted minimally with aceramido-GM1 by STD NMR. Unusually, TFR-41 rotavirus infectivity depended upon terminal Sia and GM1. Competition of CTB, Sia, and/or aceramido-GM1 with cell binding by VP8* from representative rotaviruses showed that rotavirus Sia and GM1 preferences resulted from VP8*-cell binding. Our major finding is that infection by human rotaviruses of commonly occurring VP4 serotypes involves VP8* binding to cell surface GM1 glycan, typically including the internal N-acetylneuraminic acid. IMPORTANCERotaviruses, the major cause of severe infantile gastroenteritis, recognize cell surface receptors through virus spike protein VP4. Several animal rotaviruses are known to bind sialic acids at the termini of main carbohydrate chains. Conversely, only a single human rotavirus is known to bind sialic acid. Interestingly, VP4 of this rotavirus bound to sialic acid that forms a branch on the main carbohydrate chain of the GM1 ganglioside. Here, we use several techniques to demonstrate that other human rotaviruses exhibit similar GM1 usage properties. Furthermore, binding by VP4 to cell surface GM1, involving branched sialic acid recognition, is shown to facilitate infection. In contrast, most animal rotaviruses that bind terminal sialic acids did not utilize GM1 for VP4 cell binding or infection. These studies support a significant role for GM1 in mediating host cell invasion by human rotaviruses.

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“…Существенную роль в развитии аллергии игра-ют нарушения активности различных субпопуля-ций и апоптоза лимфоцитов [1][2][3], которые могут быть исследованы с помощью оценки ýкспрессии отдельных функциональных молекул на поверх-ности лимфоцитов. Для аллергологии концеп-ция персонализированного подхода на основе трансляционной медицины наиболее ýффектив-но может быть реализована при изучении таких заболеваний, как поллиноз, бронхиальная астма, атопический дерматит.…”

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Immunopathogenesis of atopic diseases formation

Порядин¹,

Салмаси²,

Казимирский³

et al. 2017

Bûll. sib. med.

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ВВЕДЕНИЕПеренос результатов фундаментальных ис-следований из биомедицины в медицинскую практику с целью улучшения лечения и диагно-УДК 616-056. 43-097 DOI: 10.20538/168243-097 DOI: 10.20538/ -0363-2017 Для цитирования: Порядин Г.В., Салмаси Ж.М., Казимирский А.Н., Семенова Л.Ю. Иммунопатогенез формирования атопических заболеваний. Бюллетень сибирской медицины. 2017; 16 (4): 233-241. Иммунопатогенез формирования атопических заболеванийПорядин Г.В., Салмаси Ж.М., Казимирский А.Н., Семенова Л.Ю. Результаты проведенных исследований убедительно свидетельствуют, что атопические болезни разли-чаются не только клиническими проявлениями, но и механизмами нарушений функций иммунной систе-мы. Сравнительное изучение поверхностного фенотипа лимфоцитов у больных с различными формами атопии позволило выявить существенное нарастание изменений их субпопуляционного состава по мере усиления тяжести клинических проявлений заболеваний. У больных всеми исследованными формами атопии отмечалось повышение содержания в периферической крови В-лимфоцитов, экспрессирующих маркер CD72, и лимфоцитов, несущих ранние активационные антигены CD23, CD25, CD71 и рецепторы адгезии CD54. Развитие поллиноза, атопической бронхиальной астмы и атопического дерматита сопро-вождалось дополнительным повышением содержания в периферической крови лимфоцитов, экспресси-рующих поздний маркер активации HLA-DR,предшественников плазматических клеток и лимфоцитов CD38 + , несущих поверхностные иммуноглобулины. В крови у больных атопией с выраженными клини-ческими проявлениями выявлено достоверное повышение содержания всех изученных субпопуляций В-лимфоцитов. У больных с латентной сенсибилизацией зарегистрировано повышенное содержание в крови лимфоцитов, экспрессирующих CD95-рецептор запуска Fas-индуцированного апоптоза, и сни-жение количества клеток, экспрессирующих его лиганд -рецептор CD178. У больных с атопической бронхиальной астмой и атопическим дерматитом содержание в крови CD95 + лимфоцитов, напротив, снижено, а CD178 + -лимфоцитов -повышено, что отражает нарушение Fas-зависимого апоптоза при тяжелых атопических заболеваниях.Ключевые слова: атопическая бронхиальная астма, атопический дерматит, поллиноз, латентная сенсибилизация, CD-антигены.стики -одно из важнейших направлений разви-тия современной медицины. В настоящее время аллергические заболевания, имеющие в своей основе нарушения функции иммунной системы, являются ведущей причиной инвалидизации насе-ления во многих развитых странах, в том числе и в Российской Федерации. Вопросы качественной Бюллетень сибирской медицины. 2017; 16 (4): 233-241

show abstract

CD4 and CD8 T cells require different membrane gangliosides for activation

Cited by 119 publications

References 48 publications

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

Relative Roles of GM1 Ganglioside, N -Acylneuraminic Acids, and α2β1 Integrin in Mediating Rotavirus Infection

Immunopathogenesis of atopic diseases formation

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