An Essential Role for the Stalk Region of CD8β in the Coreceptor Function of CD8

Rettig, Lorna; McNeill, Louise; Sarner, Nitza; Guillaume, Philippe; Luescher, Immanuel F.; Tolaini, Mauro; Kioussis, Dimitris; Zamoyska, Rose

doi:10.4049/jimmunol.182.1.121

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…Although the role of CD8αβ as a T cell coreceptor dictates its “trans” interaction with the peptide-binding MHCI molecule on the APC, we note that the structure of the CD8αβ/MHCI complex does not eliminate the possibility of a “cis” interaction between CD8αβ and MHCI expressed on the T cell (73-76). Our structural analysis is consistent with the view that the shorter stalk of CD8β plays a crucial role in the orientation of the cytoplasmic domains of the CD8αβ heterodimer for their role in signal transduction (33). The structure of this murine CD8αβ/MHCI complex may serve as a guide to a mechanistic understanding of human CD8 mutants that result in immunodeficiency (77, 78) and provide a context for further examination of the role of the distinct domains of the CD8 molecule in binding and function.…”

Section: Discussionsupporting

confidence: 90%

“…The tail serves CD8α as an Lck docking site. The superior coreceptor activity of CD8αβ has been attributed to the stalk region of the β chain and its glycosylation (30-33) and to a palmitoylation site in the β cytoplasmic tail (11), which targets CD8αβ and the associated TCR to lipid rafts. Recent studies indicate that a conserved peptide motif of the TCR α chain connecting peptide plays a crucial role in CD8β participation in signal transduction (34).…”

Section: Introductionmentioning

confidence: 99%

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Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position

Wang

Natarajan

Margulies

2009

The Journal of Immunology

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In the immune system, B cells, dendritic cells, NK cells, and T lymphocytes all respond to signals received via ligand binding to receptors and coreceptors. Although the specificity of T cell recognition is determined by the interaction of T cell receptors with MHC/peptide complexes, the development of T cells in the thymus and their sensitivity to Ag are also dependent on coreceptor molecules CD8 (for MHC class I (MHCI)) and CD4 (for MHCII). The CD8αβ heterodimer is a potent coreceptor for T cell activation, but efforts to understand its function fully have been hampered by ignorance of the structural details of its interactions with MHCI. In this study we describe the structure of CD8αβ in complex with the murine MHCI molecule H-2Dd at 2.6 Å resolution. The focus of the CD8αβ interaction is the acidic loop (residues 222–228) of the α3 domain of H-2Dd. The β subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8α and CD8β subunits. Unlike the CD8αα homodimer, CD8αβ does not contact the MHCI α2- or β2-microglobulin domains. Movements of the CD8α CDR2 and CD8β CDR1 and CDR2 loops as well as the flexibility of the H-2Dd CD loop facilitate the monovalent interaction. The structure resolves inconclusive data on the topology of the CD8αβ/MHCI interaction, indicates that CD8β is crucial in orienting the CD8αβ heterodimer, provides a framework for understanding the mechanistic role of CD8αβ in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position

Wang

Natarajan

Margulies

2009

The Journal of Immunology

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“…The model is consistent with the idea that the shorter CD8β stalk helps orient the cytoplasmic domains of CD8αβ for their role in signal transduction (23, 79). However, in the absence of structural information on the CD8 stalk, the model cannot establish anchor points for TCR and CD8 on the T cell membrane, as did the TCR–pMHC–CD4 structure (Figure 3A).…”

Section: Implications For the Tcr–pmhc–cd8 Ternary Complexsupporting

confidence: 87%

Structural and Biophysical Insights into the Role of CD4 and CD8 in T Cell Activation

Li¹,

Yin²,

Mariuzza³

2013

Front. Immunol.

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T cell receptors (TCRs) recognize peptides presented by MHC molecules (pMHC) on an antigen-presenting cell (APC) to discriminate foreign from self-antigens and initiate adaptive immune responses. In addition, T cell activation generally requires binding of this same pMHC to a CD4 or CD8 co-receptor, resulting in assembly of a TCR–pMHC–CD4 or TCR–pMHC–CD8 complex and recruitment of Lck via its association with the co-receptor. Here we review structural and biophysical studies of CD4 and CD8 interactions with MHC molecules and TCR–pMHC complexes. Crystal structures have been determined of CD8αα and CD8αβ in complex with MHC class I, of CD4 bound to MHC class II, and of a complete TCR–pMHC–CD4 ternary complex. Additionally, the binding of these co-receptors to pMHC and TCR–pMHC ligands has been investigated both in solution and in situ at the T cell–APC interface. Together, these studies have provided key insights into the role of CD4 and CD8 in T cell activation, and into how these co-receptors focus TCR on MHC to guide TCR docking on pMHC during thymic T cell selection.

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“…To date, analyses of the effects of post-translational modifications on CAR-T cell activity are lacking. Within their original proteins, these borrowed components undergo post-translational modifications, such as disulphide bonding and glycosylation, which are known to play an important role in their function [ 8 , 9 , 10 , 11 , 12 , 13 ]. It is therefore quite likely that these moieties also undergo post-translational modification as part of the CAR construct, which would in turn affect CAR expression or CAR-T cell function.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Chimeric Antigen Receptor (CAR) Hinge Domain Post-Translational Modifications on CAR-T Cell Activity

Hirobe

Imaeda

Tachibana

et al. 2022

IJMS

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To improve the efficacy and safety of chimeric antigen receptor (CAR)-expressing T cell therapeutics through enhanced CAR design, we analysed CAR structural factors that affect CAR-T cell function. We studied the effects of disulphide bonding at cysteine residues and glycosylation in the HD on CAR-T function. We used first-generation CAR[V/28/28/3z] and CAR[V/8a/8a/3z], consisting of a mouse vascular endothelial growth factor receptor 2 (VEGFR2)-specific single-chain variable fragment tandemly linked to CD28- or CD8α-derived HD, transmembrane domain (TMD) and a CD3ζ-derived signal transduction domain (STD). We constructed structural variants by substituting cysteine with alanine and asparagine (putative N-linked glycosylation sites) with aspartate. CAR[V/28/28/3z] and CAR[V/8a/8a/3z] formed homodimers, the former through a single HD cysteine residue and the latter through the more TMD-proximal of the two cysteine residues. The absence of disulphide bonds did not affect membrane CAR expression but reduced antigen-specific cytokine production and cytotoxic activity. CAR[V/28/28/3z] and CAR[V/8a/8a/3z] harboured one N-linked glycosylation site, and CAR[V/8a/8a/3z] underwent considerable O-linked glycosylation at an unknown site. Thus, N-linked glycosylation of CAR[V/28/28/3z] promotes stable membrane CAR expression, while having no effect on the expression or CAR-T cell activity of CAR[V/8a/8a/3z]. Our findings demonstrate that post-translational modifications of the CAR HD influence CAR-T cell activity, establishing a basis for future CAR design.

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An Essential Role for the Stalk Region of CD8β in the Coreceptor Function of CD8

Cited by 6 publications

References 52 publications

Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position

Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position

Structural and Biophysical Insights into the Role of CD4 and CD8 in T Cell Activation

The Effects of Chimeric Antigen Receptor (CAR) Hinge Domain Post-Translational Modifications on CAR-T Cell Activity

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