The structural basis of αβ T‐lineage immune recognition: <scp>TCR</scp> docking topologies, mechanotransduction, and co‐receptor function

Wang, Jia-Huai; Reinherz, Ellis L.

doi:10.1111/j.1600-065x.2012.01161.x

Cited by 95 publications

(107 citation statements)

References 127 publications

(211 reference statements)

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“…3E). Bond lifetime modification by force is not unexpected (18,19,30) and is not correlated with force-free 3D (31-33) or 2D measurements (28,34). Thus, prolonged bond lifetime for M2 3 under force compared with M2 2 is not inconsistent with the solution NMR analyses, where binding is force-free and occurs in the absence of biomembrane constraints.…”

Section: Pretcrβ Subunit Displays Structural Elements With Potential Formentioning

confidence: 84%

Pre-TCR ligand binding impacts thymocyte development before αβTCR expression

Mallis

Bai

Arthanari

et al. 2015

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

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118

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Adaptive cellular immunity requires accurate self-vs. nonself-discrimination to protect against infections and tumorous transformations while at the same time excluding autoimmunity. This vital capability is programmed in the thymus through selection of αβT-cell receptors (αβTCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pTα-β heterodimer appearing before αβTCR expression, directs a previously unappreciated initial phase of repertoire selection. Contrasting with the ligandindependent model of preTCR function, we reveal through NMR and bioforce-probe analyses that the β-subunit binds pMHC using Vβ complementarity-determining regions as well as an exposed hydrophobic Vβ patch characteristic of the preTCR. Force-regulated single bonds akin to those of αβTCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential β-and then, αβ-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for β-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction.pre-T-cell receptor | NMR spectroscopy | biomembrane force probe | thymic development | repertoire selection

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Section: Pretcrβ Subunit Displays Structural Elements With Potential Formentioning

confidence: 84%

Pre-TCR ligand binding impacts thymocyte development before αβTCR expression

Mallis

Bai

Arthanari

et al. 2015

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

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118

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“…Our data provide a structural framework that can potentially begin to reconcile disparate observations about how the TCR relays a ligation event to signaling. Such observations include studies showing that monomeric pMHC possesses little to no ability to induce signaling regardless of affinity (49), there exist signaling-permissive and -nonpermissive pMHC-TCR docking geometries (48), conformational changes occur in the TCR upon pMHC ligation (46,(50)(51)(52), the CD4 and CD8 coreceptors are required to place Lck relative to the CD3 ITAMs (53, 54), phosphatases are occluded from the T-cell Ag-presenting cell synapse (18,26,55), and mechanotransduction appears to be important for TCR signaling (19,36,(56)(57)(58)(59) (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…What, if any, role interactions between TCR and CD3 ECDs play in the assembly and function of the complex remains controversial (5): there are several plausible proposed models of activation, which are not necessarily mutually exclusive (5,(17)(18)(19). Although structures of TCR-peptide-MHC (pMHC) complexes (2), TCR-MHC-I-like complexes (1), and the CD3 dimers (6-10) have been separately determined, how the αβ TCR associates with the CD3 complex is largely unknown.…”

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confidence: 99%

Molecular architecture of the αβ T cell receptor–CD3 complex

Birnbaum

Berry

Hsiao

et al. 2014

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

109

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αβ T-cell receptor (TCR) activation plays a crucial role for T-cell function. However, the TCR itself does not possess signaling domains. Instead, the TCR is noncovalently coupled to a conserved multisubunit signaling apparatus, the CD3 complex, that comprises the CD3eγ, CD3eδ, and CD3ζζ dimers. How antigen ligation by the TCR triggers CD3 activation and what structural role the CD3 extracellular domains (ECDs) play in the assembled TCR-CD3 complex remain unclear. Here, we use two complementary structural approaches to gain insight into the overall organization of the TCR-CD3 complex. Small-angle X-ray scattering of the soluble TCR-CD3eδ complex reveals the CD3eδ ECDs to sit underneath the TCR α-chain. The observed arrangement is consistent with EM images of the entire TCR-CD3 integral membrane complex, in which the CD3eδ and CD3eγ subunits were situated underneath the TCR α-chain and TCR β-chain, respectively. Interestingly, the TCR-CD3 transmembrane complex bound to peptide-MHC is a dimer in which two TCRs project outward from a central core composed of the CD3 ECDs and the TCR and CD3 transmembrane domains. This arrangement suggests a potential ligand-dependent dimerization mechanism for TCR signaling. Collectively, our data advance our understanding of the molecular organization of the TCR-CD3 complex, and provides a conceptual framework for the TCR activation mechanism.T-cell receptor | electron microscopy | small-angle X-ray scattering T cells are key mediators of the adaptive immune response.Each αβ T cell contains a unique αβ T-cell receptor (TCR), which binds antigens (Ags) displayed by major histocompatibility complexes (MHCs) and MHC-like molecules (1). The TCR serves as a remarkably sensitive driver of cellular function: although TCR ligands typically bind quite weakly (1-200 μM), even a handful of TCR ligands are sufficient to fully activate a T cell (2, 3). The TCR does not possess intracellular signaling domains, uncoupling Ag recognition from T-cell signaling. The TCR is instead noncovalently associated with a multisubunit signaling apparatus, consisting of the CD3eγ and CD3eδ heterodimers and the CD3ζζ homodimer, which collectively form the TCR-CD3 complex (4, 5). The CD3γ/δ/e subunits each consist of a single extracellular Ig domain and a single immunoreceptor tyrosine-based activation motif (ITAM), whereas CD3ζ has a short extracellular domain (ECD) and three ITAMs (6-11). The TCR-CD3 complex exists in 1:1:1:1 stoichiometry for the αβTCR: CD3eγ:CD3eδ:CD3ζζ dimers (12). Phosphorylation of the intracellular CD3 ITAMs and recruitment of the adaptor Nck lead to T-cell activation, proliferation, and survival (13,14). Understanding the underlying principles of TCR-CD3 architecture and T-cell signaling is of therapeutic interest. For example, TCR-CD3 is the target of therapeutic antibodies such as the immunosuppressant OKT3 (15), and there is increasing interest in manipulating T cells in an Ag-dependent manner by using naturally occurring and engineered TCRs (16).Assembly of the TCR-CD3 complex is p...

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“…Within the DN3 stage, a pre-TCR complex is generated comprised of a variable TCR␤ chain disulfide-linked to the invariant pT␣ subunit. In turn, the pT␣-␤ heterodimer is noncovalently complexed with the same CD3 dimers as found in the ␣␤TCR, namely CD3⑀␥, CD3⑀␦, and CD3 (1,2). This pre-TCR complex triggers cellular survival and expansion and, importantly, induces expression of CD4 and CD8 co-receptors so that the thymocytes transit to the DP (CD4 ϩ CD8 ϩ ) thymocyte stage where rearrangement of the TCR␣ gene occurs.…”

Section: And References Therein)mentioning

confidence: 99%

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands

Das

Mallis

Duke‐Cohan

et al. 2016

Journal of Biological Chemistry

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Edited by Peter CresswellThe pre-T cell receptor (pre-TCR) is a pT␣-␤ heterodimer functioning in early ␣␤ T cell development. Although once thought to be ligand-autonomous, recent studies show that preTCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the ␣␤TCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the C␤ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCR␣␤ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic V␤ patch apposition. This patch functions in the pre-TCR as a surrogate V␣ domain, fostering ligand promiscuity to favor development of ␤ chains with self-reactivity but is occluded by ␣ subunit replacement of pT␣ upon ␣␤TCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor ␣␤TCR repertoire tuning via the pre-TCR.The mammalian adaptive immune system protects its host against infectious diseases as well as tumors in a highly specific manner. At the core of ␣␤ T lymphocyte recognition is self-versus non-self-discrimination, a functionality endowed by clonal cell-surface T cell receptors (TCRs) 4 (1-3). In the mammalian thymus, the millions of distinct TCRs expressed create a repertoire that is refined to eliminate unwanted autoreactive specificities prior to export into the peripheral lymphoid compartment (Ref. 4 and references therein).The earliest thymocytes, termed double negative (DN1-4), lack both CD4 and CD8 and expression of ␣␤TCR complexes (hereafter termed ␣␤TCRs) (5). Within the DN3 stage, a pre-TCR complex is generated comprised of a variable TCR␤ chain disulfide-linked to the invariant pT␣ subunit. In turn, the pT␣-␤ heterodimer is noncovalently complexed with the same CD3 dimers as found in the ␣␤TCR, namely CD3⑀␥, CD3⑀␦, and CD3 (1, 2). This pre-TCR complex triggers cellular survival and expansion and, importantly, induces expression of CD4 and CD8 co-receptors so that the thymocytes transit to the DP (CD4 ϩ CD8 ϩ ) thymocyte stage where rearrangement of the TCR␣ gene occurs. Only at the DP stage is the ␣␤TCR expressed. The pre-TCR signaling process, termed ␤ selection, also controls allelic exclusion of the TCR␤ locus in a given cell (6). Pre-TCR signaling components include tyrosine kinases Lck, Fyn, with Notch-1, Notch-1 ligand DL4, interleukin 7, and CXCR4 supporting pre-TCR function (5, 10). Although ␣␤TCR DP thymocyte selection processes involve pMHC-dependent posit...

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The structural basis of αβ T‐lineage immune recognition: TCR docking topologies, mechanotransduction, and co‐receptor function

Cited by 95 publications

References 127 publications

Pre-TCR ligand binding impacts thymocyte development before αβTCR expression

Pre-TCR ligand binding impacts thymocyte development before αβTCR expression

Molecular architecture of the αβ T cell receptor–CD3 complex

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands

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