A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation

Swamy, Mahima; Beck-García, Katharina; Beck-García, Esmeralda; Hartl, Frederike A.; Morath, Anna; Yousefi, O. Sascha; Dopfer, Elaine P.; Molnár, Éva D.; Schulze, Anna; Blanco, Raquel; Borroto, Aldo; Martín-Blanco, Nadia; Alarcón, Balbino; Höfer, Thomas; Minguet, Susana; Schamel, Wolfgang W. A.

doi:10.1016/j.immuni.2016.04.011

Cited by 192 publications

(199 citation statements)

References 56 publications

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“…The function of this acidic TM residue is unknown (discussed in ref. 16), but its location identifies the "exposed" TCRβ helix face as a region of interest in potential oligomeric TCR interactions (43)(44)(45) and associations with particular lipid or sterol moieties that have been shown to regulate receptor activation (46,47). Several groups have proposed models of TCR-CD3 arrangements based on extracellular domain interactions.…”

Section: Discussionmentioning

confidence: 99%

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

Krshnan

Park

et al. 2016

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

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The T-cell antigen receptor (TCR) is an assembly of eight type I single-pass membrane proteins that occupies a central position in adaptive immunity. Many TCR-triggering models invoke an alteration in receptor complex structure as the initiating event, but both the precise subunit organization and the pathway by which ligandinduced alterations are transferred to the cytoplasmic signaling domains are unknown. Here, we show that the receptor complex transmembrane (TM) domains form an intimately associated eighthelix bundle organized by a specific interhelical TCR TM interface. The salient features of this core structure are absolutely conserved between αβ and γδ TCR sequences and throughout vertebrate evolution, and mutations at key interface residues caused defects in the formation of stable TCRαβ:CD3δe:CD3γe:ζζ complexes. These findings demonstrate that the eight TCR-CD3 subunits form a compact and precisely organized structure within the membrane and provide a structural basis for further investigation of conformationally regulated models of transbilayer TCR signaling.T-cell receptor | transmembrane structure | NMR | MD simulation | cysteine cross-linking T he antigen-specific T-cell response depends critically upon the ability of the T-cell receptor (TCR) to signal the recognition of activating ligands. The variable TCR proteins (α, β, δ, and γ) that bind to these ligands have no intrinsic intracellular signaling capability and transmit information through the noncovalently associated CD3δe, CD3γe, and ζζ modules containing cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) that are phosphorylated by the Src-family kinase Lck. The mechanism by which antigen sensing is translated from ligand binding at the distal end of the TCR to phosphorylation events at the cytoplasmic tails of the associated signaling modules remains an important open question in T-cell biology. A mounting pool of evidence implicates ligand-induced alterations in receptor structure (1) and/or TCR-CD3 configuration (2-6) as the triggering event. Changes in the structured extracellular (EC) domains are proposed to translate, through an unknown mechanism, into alterations in the CD3 and ζζ cytoplasmic tails, converting them to a conformation that is receptive to phosphorylation by Lck and binding of other proximal signaling components (7-12). This type of signaling model implies a pathway between EC and cytoplasmic domains that may involve alterations in the subunit transmembrane (TM) domains with respect to each other and/ or the lipid bilayer (13-16). Consistent with this view, Kuhns and colleagues (17) recently reported a ligand-induced change in intersubunit proximity at the TM-juxtamembrane juncture in the ζζ dimer and proposed that this "mechanical switch" is coupled to signal initiation at the ζζ cytoplasmic tails. However, the nature of the upstream structural changes that trigger this switch, and whether it is required for signal initiation, remain to be determined. Tracing possible transbilayer conformational pathway...

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Section: Discussionmentioning

confidence: 99%

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

Krshnan

Park

et al. 2016

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

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“…Interestingly, cholesterol may serve temporal or spatial roles in TCR signaling. Cholesterol is an allosteric inhibitor of the TCRβ transmembrane domain and hence limits spontaneous TCR activation; however, the spontaneous unbinding of cholesterol in this region switches the conformation from inactive to active, allowing for the transmission of TCR signals (81). Therefore, cholesterol level in the plasma membrane of T cells is important for regulating TCR activity, which may contribute to T cell development and functions under different conditions.…”

Section: Lipid Sensingmentioning

confidence: 99%

Nutrient and Metabolic Sensing in T Cell Responses

et al. 2017

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T cells play pivotal roles in shaping host immune responses in infectious diseases, autoimmunity, and cancer. The activation of T cells requires immune and growth factor-derived signals. However, alterations in nutrients and metabolic signals tune T cell responses by impinging upon T cell fates and immune functions. In this review, we summarize how key nutrients, including glucose, amino acids, and lipids, and their sensors and transporters shape T cell responses. We also briefly discuss regulation of T cell responses by oxygen and energy sensing mechanisms.

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“…The extent to which Sult2b1-derived cholesterol sulfate may serve as a dynamic negative feedback regulator of TCR activation in vivo is uncertain, but evidence does suggest that it plays a role in thymic selection through differential regulation of TCR signaling in thymic T cell subsets [70]. Adding yet further complexity to the picture, it was recently reported that cholesterol binding may serve a dual role in TCR signaling, promoting TCR avidity, but also restraining spontaneous signaling by keeping the TCR in an inactive allosteric conformation that cannot be phosphorylated [71]. Taken together, it appears that cholesterol and its metabolites may serve to fine-tune the setpoint for TCR activation, possibly in a developmental, cell-specific, and stimulus-dependent manner.…”

Section: Dynamic Sterol Fluxes Regulate T Cell Immunitymentioning

confidence: 99%

The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

Fessler

2016

Trends in Immunology

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Cholesterol has typically been considered an exogenous, disease-related factor in immunity; however, recent literature suggests that a paradigm shift is in order. Sterols are now recognized to ligate several immune receptors. Altered flux through the mevalonic acid synthesis pathway also appears to be a required event in the antiviral interferon response of macrophages and in the activation, proliferation, and differentiation of T cells. In this review, evidence is discussed that suggests an intrinsic, ‘professional’ role for sterols and oxysterols in macrophage and T cell immunity. Host defense may have been the original selection pressure behind the development of mechanisms for intracellular cholesterol homeostasis. Functional coupling between sterol metabolism and immunity has fundamental implications for health and disease.

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A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation

Cited by 192 publications

References 56 publications

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

Nutrient and Metabolic Sensing in T Cell Responses

The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

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