Phosphatidylserine-Induced Conformational Modulation of Immune Cell Exhaustion-Associated Receptor TIM3

Weber, Jeffrey K.; Zhou, Ruhong

doi:10.1038/s41598-017-14064-x

Cited by 9 publications

(14 citation statements)

References 38 publications

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“…The predicted TIM3–PS binding site and binding pose are consistent with the experimental results . Furthermore, similar to the molecular dynamics simulation results from Weber and Zhou, the TIM3–PS system also experiences some opening of the FG–CC′ cleft as illustrated in Figure d and Figure S5.…”

Section: Resultssupporting

confidence: 85%

“…To demonstrate our method, we first studied the binding of phosphatidylserine (PS) with the extracellular IgV domain of TIM3. Only the IgV domain is simulated in this research to reduce the computational cost, and also, it is known that both PS and Galectin-9 bind to this domain in particular. , TIM3-PS binding is thought to play a role in supporting immune cell tolerance, but not much is known about how TIM3–PS binding triggers the immune cell tolerance except for the TIM3–PS binding site . Regardless, the TIM3–PS system will be approached as though no prior knowledge of the TIM3–PS binding site is available, except for the fact that PS binding is calcium-ion-dependent.…”

Section: Resultsmentioning

confidence: 99%

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Prediction of the Peptide–TIM3 Binding Site in Inhibiting TIM3–Galectin 9 Binding Pathways

Odstrcil,

Dutta,

Liu

2023

J. Chem. Theory Comput.

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T-cell immunoglobulin and mucin domain-containing protein-3 (TIM3) is an important receptor protein that modulates the immune system. The binding of TIM3 with Galectin 9 (GAL9) triggers immune system suppression, but the TIM3−GAL9 binding can be inhibited by binding of the peptide P26 to TIM3. A fast and accurate prediction of the P26-TIM3 binding site is crucial and a prerequisite for the investigation of P26−TIM3 interactions and TIM3−GAL9 binding pathways. Here, we present a machine learning approach, which considers protein conformational changes, to quickly identify the ligand-binding site on TIM3. Our results show that the P26 binding site is located near the C″−D loop of TIM3. Further simulations show that the binding pose is stabilized by a variety of electrostatic and hydrophobic interactions. Binding of P26 can alter the conformations of nearby glycan side chains on TIM3, providing possible mechanisms of how P26 inhibits TIM3−GAL9 binding pathways. The insights from this work will facilitate the identification of other peptides or antibodies that may also inhibit the TIM3−GAL9 pathways and eventually lead to improved attempts in the modulation of the TIM3−GAL9 immunosuppression pathways. The strategies and machine learning method can be generalized to study ligand−receptor binding when the conformational changes during the binding are important.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Prediction of the Peptide–TIM3 Binding Site in Inhibiting TIM3–Galectin 9 Binding Pathways

Odstrcil,

Dutta,

Liu

2023

J. Chem. Theory Comput.

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“…They have been known as high affinity PS-binding receptors that directly interact with PS [12]. In contrast, TIM-3 and PS interaction has been proposed [49], but has not been extensively verified. Specifically, TIM4 has been shown to be involved in the process of efferocytosis and is ubiquitously expressed in macrophages [12,50].…”

Section: Discussionmentioning

confidence: 99%

Evaluating the differential expression of TAM family receptors and efferocytosis activities in differentiated and polarized THP-1 macrophage

Chamberland

Farrell

Yeh

2022

Preprint

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Tissue homeostasis is tightly balanced between cell death and renewal. Each day, as many as 1011 cells die in the human body that need to be removed and replaced. The clearance of apoptotic cells, termed efferocytosis, is crucial to tissue homeostasis. Central to this process is macrophage-mediated efferocytosis. Apart from general phagocytosis, efferocytosis is apoptotic cell-specific, which aids in clearing dead cells and preventing the accumulation of self-antigens released by the apoptotic cells. The TAM family receptor kinases (TYRO3, AXL, MERTK) and ligands (GAS6 and PROS) play important roles in engaging the apoptotic cells to initiate efferocytic engulfment and the downstream cellular responses. Dysregulated efferocytic function in macrophages is associated with human diseases such as atherosclerosis, lupus, lung fibrosis, and cancer. Conversely, understanding the regulation and molecular mechanisms of macrophage efferocytosis can potentially lead to beneficial treatments for the above diseases. Despite numerous efferocytosis studies that use primary and cell line-derived macrophages, there has not been a thorough characterization of a cell line system that can be reliably used for efferocytosis assays. Consequently, many macrophage efferocytosis assays reported do not clearly distinguish efferocytosis from phagocytosis. Here we evaluated the THP-1 cell line as a potential human macrophage cell line system for efferocytosis studies. Consequently, many macrophage efferocytosis assays reported do not clearly distinguish efferocytosis from phagocytosis. Through the study we examined the differential expression of the TAM family receptors and their ligands in the various THP-1 macrophage differentiation and polarization states. We also characterized the THP-1 cell line as a reliable system for performing in vitro efferocytosis studies.

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“…Similarly, engagement of TIM-3 by the carbohydrate Galectin-9 [ 375 ], generated by various cell types [ 381 , 382 , 383 , 384 ], induced Th1 effector cell apoptosis [ 375 ]. On the contrary, binding of TIM-3 to PS [ 385 ], characteristic for apoptotic cells [ 386 ], enhanced T-cell activity [ 387 ]. With regard to other cell types, TIM-3/Galectin-9 ligation was reported to either promote DC [ 388 ] and NK cell [ 389 ] activity, and to favor expansion of DCs and NKT cells [ 390 ].…”

Section: Emerging Immune Checkpoints and Their Impact On Non-t-cell I...mentioning

confidence: 99%

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

Kuske

Haist

Jung

et al. 2022

Cancers

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The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40–60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment.

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Phosphatidylserine-Induced Conformational Modulation of Immune Cell Exhaustion-Associated Receptor TIM3

Cited by 9 publications

References 38 publications

Prediction of the Peptide–TIM3 Binding Site in Inhibiting TIM3–Galectin 9 Binding Pathways

Prediction of the Peptide–TIM3 Binding Site in Inhibiting TIM3–Galectin 9 Binding Pathways

Evaluating the differential expression of TAM family receptors and efferocytosis activities in differentiated and polarized THP-1 macrophage

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

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