Apoptotic Cells Activate NKT Cells through T Cell Ig-Like Mucin-Like–1 Resulting in Airway Hyperreactivity

Lee, Hyun Hee; Meyer, Everett; Goya, Sho; Pichavant, Muriel; Kim, Hye Young; Bu, Xia; Umetsu, Sarah E.; Jones, Jennifer C.; Savage, Paul B.; Iwakura, Yoichiro; Casasnovas, José M.; Kaplan, Gerardo; Freeman, Gordon J.; DeKruyff, Rosemarie H.; Umetsu, Dale T.

doi:10.4049/jimmunol.1001116

Cited by 75 publications

(95 citation statements)

References 70 publications

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“…As an example, it has now been shown that Tim1 can use apoptotic cells exposing PS as a nonphagocytic signal to produce proliferation in natural killer T cells (11). Thus, it seems plausible that the as-yet-unidentified target of Tim1 for facilitating proliferation, when expressed on conventional T cells, may also be membrane PS, exposed either by the activated T cells themselves or possibly on the antigenpresenting cells.…”

Section: Discussionmentioning

confidence: 99%

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Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

Tietjen¹,

Gong

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Recognition of phosphatidylserine (PS) lipids exposed on the extracellular leaflet of plasma membranes is implicated in both apoptotic cell removal and immune regulation. The PS receptor T cell immunoglobulin and mucin-domain-containing molecule 4 (Tim4) regulates T-cell immunity via phagocytosis of both apoptotic (high PS exposure) and nonapoptotic (intermediate PS exposure) activated T cells. The latter population must be removed at lower efficiency to sensitively control immune tolerance and memory cell population size, but the molecular basis for how Tim4 achieves this sensitivity is unknown. Using a combination of interfacial X-ray scattering, molecular dynamics simulations, and membrane binding assays, we demonstrate how Tim4 recognizes PS in the context of a lipid bilayer. Our data reveal that in addition to the known Ca 2+ -coordinated, single-PS binding pocket, Tim4 has four weaker sites of potential ionic interactions with PS lipids. This organization makes Tim4 sensitive to PS surface concentration in a manner capable of supporting differential recognition on the basis of PS exposure level. The structurally homologous, but functionally distinct, Tim1 and Tim3 are significantly less sensitive to PS surface density, likely reflecting the differences in immunological function between the Tim proteins. These results establish the potential for lipid membrane parameters, such as PS surface density, to play a critical role in facilitating selective recognition of PSexposing cells. Furthermore, our multidisciplinary approach overcomes the difficulties associated with characterizing dynamic protein/membrane systems to reveal the molecular mechanisms underlying Tim4's recognition properties, and thereby provides an approach capable of providing atomic-level detail to uncover the nuances of protein/membrane interactions. differential membrane recognition | PS recognition

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Section: Discussionmentioning

confidence: 99%

“…Moreover, there exists a wide array of structurally diverse PS receptors, the expression of which is not strictly limited to immune cells capable of phagocytosis (8,9). Accordingly, recognition of exposed PS is not always sufficient for phagocytosis (10) and can actually elicit a nonphagocytic response, such as immune cell proliferation (11).…”

mentioning

confidence: 99%

Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

Tietjen¹,

Gong

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…77,183 Defects in NKT cell function have been associated with autoimmune diseases and microbial susceptibility, reduced cell-mediated anti-tumor activity, and NKT cells may have a role in the progression of asthma. 26,27,46,49,50,64,82,88,115 In addition, TCRB-V8 has been demonstrated to serve as a receptor for exogenous MMTV, and defects in this receptor may promote immunity to lentivirus infections. 161 For further discussions on the unique immune profile of SJL mice, see reference 48.…”

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confidence: 99%

Immunological Variation Between Inbred Laboratory Mouse Strains

et al. 2011

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Inbred laboratory mouse strains are highly divergent in their immune response patterns as a result of genetic mutations and polymorphisms. The generation of genetically engineered mice (GEM) has, in the past, used embryonic stem (ES) cells for gene targeting from various 129 substrains followed by backcrossing into more fecund mouse strains. Although common inbred mice are considered ''immune competent,'' many have variations in their immune system-some of which have been described-that may affect the phenotype. Recognition of these immune variations among commonly used inbred mouse strains is essential for the accurate interpretation of expected phenotypes or those that may arise unexpectedly. In GEM developed to study specific components of the immune system, accurate evaluation of immune responses must take into consideration not only the gene of interest but also how the background strain and microbial milieu contribute to the manifestation of findings in these mice. This article discusses points to consider regarding immunological differences between the common inbred laboratory mouse strains, particularly in their use as background strains in GEM.

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“…Mice expressing defective TIM‐1 fail to phagocytose apoptotic cells in acute renal injury consistent with the critical role of TIM‐1 in efferocytosis 52. Unlike 3B3 and 3D10 agonist antibody clones, RMT1‐10 does not block binding of phosphatidylserine‐expressing apoptotic cells to TIM‐1‐expressing phagocytes53 indicating a potential role of RMT1‐10 in facilitating efferocytosis. It is supported by our results where RMT1‐10 treatment improves lesion efferocytosis and with the results of Foks et al where 3D3 treated mice showed increased apoptosis and impaired effecrocytosis in 3B3 treated mice 42…”

Section: Discussionmentioning

confidence: 61%

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Hosseini

Kanellakis

et al. 2018

JAHA

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BackgroundPeritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T‐cell immunoglobulin mucin domain‐1 (TIM‐1) expanded through TIM‐1 ligation by anti‐TIM‐1 monoclonal antibody (RMT1‐10) induces immune tolerance.Methods and ResultsWe examined the capacity of RMT1‐10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1‐10 treatment selectively doubled peritoneal B1a cells, tripled TIM‐1+ B1a cells and increased TIM‐1+IgM+interleukin (IL)‐10+ by 3‐fold and TIM‐1+IgM+IL‐10− B1a cells by 2.5‐fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low‐density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, expression of proinflammatory cytokines monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1‐10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell‐dependent. Apolipoprotein E‐KO mice fed a high‐fat diet for 6 weeks before treatment with RMT1‐10 also increased TIM‐1+IgM+ IL‐10+ and TIM‐1+IgM+ IL‐10− B1a cells and IgM levels and attenuated progression of established atherosclerosis.Conclusions RMT1‐10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody‐based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.

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Apoptotic Cells Activate NKT Cells through T Cell Ig-Like Mucin-Like–1 Resulting in Airway Hyperreactivity

Cited by 75 publications

References 70 publications

Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

Immunological Variation Between Inbred Laboratory Mouse Strains

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

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