Cooperativity Between T Cell Receptor Complexes Revealed by Conformational Mutants of CD3ɛ

Martínez, Núria; Risueño, Ruth M.; Morreale, Antonio; Zaldívar, Irene; Fernández‐Arenas, Elena; Herranz, Fernando; Ortíz, Ángel R.; Alarcón, Balbino

doi:10.1126/scisignal.2000402

Cited by 95 publications

(106 citation statements)

References 44 publications

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“…The separation of the dimerization interface and the surfaces mediating TCR-CD3 interactions obviates the need for moving one or more of the CD3 heterodimers to expose a dimerization site on the αβTCR (12). Also, the finding that the CD3ε chains are adjoined may have implications for the recent observation of coordinated signaling between the CD3ε chains within a complex (36).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a functional sidedness to the αβTCR

Kuhns

Girvin

Klein

et al. 2010

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

124

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The T cell receptor (TCR) and associated CD3γε, δε, and ζζ signaling dimers allow T cells to discriminate between different antigens and respond accordingly, but our knowledge of how these parts fit and work together is incomplete. In this study, we provide additional evidence that the CD3 heterodimers congregate on one side of the TCR in both the αβ and γδTCR-CD3 complexes. We also report that the other side of the αβTCR mediates homotypic αβTCR interactions and signaling. Specifically, an erythropoietin receptor-based dimerization assay was used to show that, upon complex assembly, the CD3ε chains of two CD3 heterodimers are arranged side-by-side in both the αβ and γδTCR-CD3 complexes. This system was also used to show that αβTCRs can dimerize in the cell membrane and that mutating the unusual outer strands of the Cα domain impairs this dimerization. Finally, we present data showing that, for CD4 T cells, the mutations that impair αβTCR dimerization also alter ligand-induced calcium mobilization, TCR accumulation at the site of pMHC contact, and polarization toward the site of antigen contact. These data reveal a "functional-sidedness" to the αβTCR constant region, with dimerization occurring on the side of the TCR opposite from where the CD3 heterodimers are located.D iscriminating among composite surfaces of peptides and major histocompatibility molecules (pMHCs) is critical for αβT cell fate decisions. The T cell receptor (TCR) α and β chains have clonotypic variable (Vα, Vβ) domains that specifically bind pMHC via low affinity interactions (1, 2), while the constant (Cα, Cβ) domains, connecting peptides, and transmembrane domains interact with the CD3γε, δε, and ζζ signaling subunits (3-7) that relay information to the intracellular signaling machinery via immunoreceptor tyrosine activation motifs (ITAMs) (8).How information transits from the TCR-pMHC interface to the ITAMs is not well understood. Residues that stabilize TCR-CD3 interactions have been implicated in signaling (6,7,9) and subtle conformational changes have been proposed (10). In addition, dimerization of the complex is thought to be important because forcing TCRs into juxtaposition can induce signaling (11, 12); however, the evidence for dimerization has been controversial (13-16), and the structural features that would mediate such interactions have not been identified. A more complete understanding of how the subunits fit together within and between complexes is needed to advance our understanding of how this molecular machinery works.Mutagenesis data indicate that both CD3 heterodimers are clustered on the side of the TCR constant domain that includes the Cα DE and Cβ CC' loops (7), leaving the outer strands of the Cα domain unobstructed. This Cα surface is a prime candidate for participating in TCR dimerization because it is structurally distinct from the analogous domains of antibodies or the γδTCR (2, 17) (Fig. S1) and the evolutionary pressures that drive the divergence of related proteins often produce variable parts of related folds...

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Section: Discussionmentioning

confidence: 99%

Evidence for a functional sidedness to the αβTCR

Kuhns

Girvin

Klein

et al. 2010

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

124

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“…The relevance of allosteric regulation in TCR triggering is supported by the findings that antigen-induced conformational changes have been observed in both extracellular and cytoplasmic domains [23,24,34,75]. Moreover, mutating CD3ε stalk region to prevent outside-in conformational transition leads to impaired TCR signaling [18,19,37]. On the other hand, mechanical force generated after T cell-APC conjugation might also affect the binding kinetics between CD3 cytoplasmic domains and the membrane [42,44].…”

Section: Discussionmentioning

confidence: 50%

“…Third, the conserved cysteine motif in the CD3 stalk regions maintains the conformations of CD3 transmembrane and cytoplasmic domains [36]. Mutation of a Cys residue in the CD3ε stalk region to prevent the outside-in conformational transition leads to the blockade of αβ T cell development and impaired peripheral T cell function due to abnormal pre-TCR and TCR signaling [18,19,37]. Fourth, mechanical force has been shown to be critical for TCR signaling and might directly cause CD3 conformational change [2,[38][39][40][41][42][43][44].…”

Section: Introductionmentioning

confidence: 99%

“…Earlier biochemical studies show that different antigens can trigger distinct ITAM phosphorylation programs [16]. Besides the ITAM, other motifs in CD3 cytoplasmic domains also play important roles in TCR signaling, including the lipid-interacting Basic residue Rich Sequence (BRS) in CD3ε and CD3ζ chains and the Nck-interacting Proline-Rich Sequence (PRS) in CD3ε chain [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. The physiological importance of BRS and PRS has been demonstrated by in vivo experiments [25,28,33].…”

Section: Introductionmentioning

confidence: 99%

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Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor

Guo

Yan

et al. 2017

Cell Res

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T-cell receptor-CD3 complex (TCR) is a versatile signaling machine that can initiate antigen-specific immune responses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3ε cytoplasmic domain (CD3ε CD ). At the single-molecule level, we found that CD3ε CD could have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3ε CD had heterogeneous lipid-binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3ε CD at different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR.

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“…Inhibition of ACAT1, a cholesterol esterification enzyme, led to increased CD8 + T cell cytotoxicity, TCR clustering, and TCR signaling (57). Further, cholesterol binds to the TCR-β chain (58), and the ratio of cholesterol to inhibitory cholesterol derivatives can potentiate TCR-mediated activation (59).…”

Section: Hfd Hyperlipidemia and Alloimmunitymentioning

confidence: 99%