Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8+ T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I. The TAPBPR/MHC-I interaction is reversed by specific peptides, related to their affinity. Mutational and small-angle X-ray scattering (SAXS) studies confirm the structural similarities of TAPBPR with tapasin. These results support a role of TAPBPR in stabilizing peptide-receptive conformation(s) of MHC-I, permitting peptide editing.

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Crystallization and preliminary X-ray diffraction analysis of the two distinct types of zebrafish β2-microglobulin

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x15005737 ◽

2015 ◽

Vol 71 (6) ◽

pp. 794-798 ◽

Cited By ~ 1

Author(s):

Zhaosan Chen ◽

Nianzhi Zhang ◽

Shuangshuang Lu ◽

Mansoor Tariq ◽

Junya Wang ◽

...

Keyword(s):

Cytotoxic T Lymphocyte ◽

Relevant Information ◽

X Ray Diffraction ◽

Unit Cell Parameters ◽

Class I Mhc ◽

Mhc I ◽

X Ray ◽

Cell Parameters ◽

Histocompatibility Complex ◽

Ctl Immune Response

β2-Microglobulin (β2m) noncovalently associates with the heavy chain of major histocompatibility complex class I (MHC I) molecules, which bind foreign antigen peptides to control the cytotoxic T lymphocyte (CTL) immune response. In contrast to mammals, there are distinct types of β2ms derived from two loci in a number of teleost species. In order to clarify the structures of the β2ms, the zebrafish (Danio rerio) β2msDare-β2m-I andDare-β2m-II were expressed inEscherichia coli, purified and crystallized, and diffraction data were collected to 1.6 and 1.9 Å resolution, respectively. Both crystals belonged to space groupP212121. The unit-cell parameters were determined to bea= 38.2,b= 50.4,c= 50.9 Å forDare-β2m-I anda= 38.9,b= 52.7,c= 65.8 Å forDare-β2m-II. Each asymmetric unit was constituted of one molecule, with Matthews coefficients of 2.22 and 3.01 Å3 Da−1and solvent contents of 45 and 59% forDare-β2m-I andDare-β2m-II, respectively. These two β2m structures will provide relevant information for further studies of the structures of the MHC I complex.

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Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease

10.1101/2020.03.04.973487 ◽

2020 ◽

Cited By ~ 1

Author(s):

Adriaan van der Graaf ◽

Maria Zorro ◽

Annique Claringbould ◽

Urmo Vosa ◽

Raul Aguirre-Gamboa ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

T Cell Activation ◽

Antigen Processing ◽

Cell Activation ◽

Association Studies ◽

Genome Wide Association Studies ◽

Master Regulator ◽

Mhc I

AbstractBackgroundCeliac disease (CeD) is a complex T cell–mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD.ResultsWe used four different in silico approaches – Mendelian Randomization inverse variance weighting, COLOC, LD overlap and DEPICT – to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signalling and T cell activation pathways. 51 of these genes are targets of known drug compounds and likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene-combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAFD1, and were found to be involved in IFNγ signalling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments that validated the role of TRAFD1 as an immune regulator acting in trans.ConclusionsOur strategy has confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and the IFNγ signalling and MHC I antigen processing pathways, both major players of immune activation and CeD pathogenesis.

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Role of membrane immunoglobulin (Ig) crosslinking in membrane Ig-mediated, major histocompatibility-restricted T cell-B cell cooperation.

Journal of Experimental Medicine ◽

10.1084/jem.162.5.1695 ◽

1985 ◽

Vol 162 (5) ◽

pp. 1695-1708 ◽

Cited By ~ 82

Author(s):

H P Tony ◽

N E Phillips ◽

D C Parker

Keyword(s):

T Cell ◽

B Cell ◽

Antigen Presentation ◽

T Cell Activation ◽

Cell Activation ◽

B Cell Activation ◽

Major Histocompatibility ◽

Class I Mhc ◽

T Cell Help

Resting murine B lymphocytes can present rabbit anti-Ig to T cell lines specific for normal rabbit globulin. The T cell-B cell interaction is major histocompatibility complex (MHC)-restricted, and leads to activation, proliferation, and differentiation of the resting B cell into an antibody-secreting cell. Efficient antigen presentation and B cell activation depends upon binding of rabbit globulin to (membrane) mIg. To investigate the role of mIg in this polyclonal model for a T cell-dependent primary antibody response, we determined whether crosslinking of mIg is required either for efficient antigen presentation, as measured by helper T cell activation, or for the B cell response to T cell help, since all the direct effects of anti-Ig on B cells require crosslinking of mIg. We found that monovalent Fab' fragments of anti-IgM or anti-IgD work as efficiently as their divalent counterparts. Therefore, a signal transduced through the antigen receptor seems not to be required when T cell help is provided by an MHC-restricted T helper cell recognizing antigen on the B cell surface. Moreover, rabbit globulin bound to class I MHC molecules in the form of anti-H-2K also results in efficient antigen presentation and T cell-dependent B cell activation. However, mIg still appears to be specialized for antigen presentation, since anti-Ig is presented about three- to fivefold more efficiently than anti-H-2K.

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Potent T Cell Activation with Dimeric Peptide–Major Histocompatibility Complex Class II Ligand: The Role of CD4 Coreceptor

Journal of Experimental Medicine ◽

10.1084/jem.188.9.1633 ◽

1998 ◽

Vol 188 (9) ◽

pp. 1633-1640 ◽

Cited By ~ 85

Author(s):

Abdel Rahim A. Hamad ◽

Sean M. O'Herrin ◽

Michael S. Lebowitz ◽

Ananth Srikrishnan ◽

Joan Bieler ◽

...

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Major Histocompatibility ◽

Histocompatibility Complex

The interaction of the T cell receptor (TCR) with its cognate peptide–major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR–MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC–TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC–TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide–MHC complex. These peptide-MHC–IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo.

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DC-SIGN promotes exogenous MHC-I–restricted HIV-1 antigen presentation

Blood ◽

10.1182/blood-2003-07-2532 ◽

2004 ◽

Vol 103 (7) ◽

pp. 2648-2654 ◽

Cited By ~ 145

Author(s):

Arnaud Moris ◽

Cinzia Nobile ◽

Florence Buseyne ◽

Françoise Porrot ◽

Jean-Pierre Abastado ◽

...

Keyword(s):

Antigen Presentation ◽

Cytotoxic T Lymphocytes ◽

Viral Envelope ◽

Class I Mhc ◽

Mhc I ◽

High Affinity ◽

Histocompatibility Complex ◽

Anti Hiv ◽

Hiv 1

Abstract Dendritic cells (DCs) facilitate HIV-1 spread in the host by capturing virions and transferring them to permissive lymphocytes in lymphoid organs. Lectins such as DC-specific ICAM-grabbing non-integrin (DC-SIGN) are involved in HIV-1 uptake by DCs, through high-affinity binding to viral envelope glycoproteins. We examined the role of DC-SIGN on the fate of incoming virions and on major histocompatibility complex class I (MHC-I)–restricted HIV-1 antigen presentation. We show that DC-SIGN expression in B-cell lines dramatically enhances viral internalization. In these cells, and also in primary DCs, most of the captured virions are rapidly degraded, likely in a lysosomal compartment. In addition, a fraction of incoming viral material is processed by the proteasome, leading to activation of anti–HIV-specific cytotoxic T lymphocytes (CTLs) by DC-SIGN–expressing cells. In DCs, DC-SIGN is not the only receptor involved, and redundant pathways of virus capture leading to antigen presentation likely coexist. Altogether, our results highlight new aspects of DC-SIGN interactions with HIV-1. The lectin does not significantly protect captured virions against degradation and promotes MHC-I exogenous presentation of HIV-1 antigens.

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Fluctuations in TCR and pMHC interactions regulate T cell activation

10.1101/2021.02.09.430441 ◽

2021 ◽

Author(s):

Joseph R. Egan ◽

Tim Elliott ◽

Ben D. MacArthur

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Information Theoretic ◽

Histocompatibility Complex ◽

Copy Numbers ◽

Stochastic Fluctuations ◽

Antigen Presenting

ABSTRACTAdaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major-histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs) respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR clustering. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell per se that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.

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Light control of the peptide-loading complex synchronizes antigen translocation and MHC I trafficking

Communications Biology ◽

10.1038/s42003-021-01890-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Jamina Brunnberg ◽

Valentina Herbring ◽

Esteban Günther Castillo ◽

Heike Krüger ◽

Ralph Wieneke ◽

...

Keyword(s):

Antigen Presentation ◽

Antigen Processing ◽

Adaptive Immune Response ◽

Class I Mhc ◽

Mhc I ◽

Atp Binding Site ◽

Histocompatibility Complex ◽

Peptide Loading ◽

Cellular Pathways ◽

Cancerous Cells

AbstractAntigen presentation via major histocompatibility complex class I (MHC I) molecules is essential to mount an adaptive immune response against pathogens and cancerous cells. To this end, the transporter associated with antigen processing (TAP) delivers snippets of the cellular proteome, resulting from proteasomal degradation, into the ER lumen. After peptide loading and editing by the peptide-loading complex (PLC), stable peptide-MHC I complexes are released for cell surface presentation. Since the process of MHC I trafficking is poorly defined, we established an approach to control antigen presentation by introduction of a photo-caged amino acid in the catalytic ATP-binding site of TAP. By optical control, we initiate TAP-dependent antigen translocation, thus providing new insights into TAP function within the PLC and MHC I trafficking in living cells. Moreover, this versatile approach has the potential to be applied in the study of other cellular pathways controlled by P-loop ATP/GTPases.

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The full model of the pMHC-TCR-CD3 complex: a structural and kinetics characterization

10.1101/2020.11.26.397687 ◽

2020 ◽

Author(s):

Josephine Alba ◽

Oreste Acuto ◽

Marco D’Abramo

Keyword(s):

T Cell ◽

T Cell Activation ◽

Bound States ◽

Cell Activation ◽

Complex Structure ◽

Cytotoxic T Cell ◽

Full Model ◽

Class I Mhc ◽

Mhc I ◽

Triggering Process

AbstractThe machinery involved in cytotoxic T-cell activation requires three main characters such as: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3-complex which is a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied both in experimental and computational models, giving a contribution in understanding the complexity of the TCR triggering process. Nevertheless, a detailed study of the structural and dynamical characterization of the full complex (pMHC:TCR:CD3-complex) is still missing, due to insufficient data available on the CD3-chains arrangement around the TCR. The recent determination of the TCR:CD3-complex structure by means of Cryo-EM technique has given a chance to build the entire proteins system essential in the activation of T-cell, and thus in the adaptive immune response. Here, we present the first full model of the pMHC interacting with the TCR:CD3-complex, built in a lipid environment. To describe the conformational behaviour associated with the unbound and the bound states, all atoms Molecular Dynamics simulations were performed for the TCR:CD3-complex and for two pMHC:TCR:CD3-complex systems, bound to two different peptides. Our data point out that a conformational change affecting the TCR Constant β (Cβ) region occurs after the binding to the pMHC, revealing a key role of such a region in the propagation of the signal. Moreover, we found that the TCR reduces the flexibility of the MHC I binding groove, confirming our previous results.

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