Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Anikeeva, Nadia; Fischer, Nicholas O.; Blanchette, Craig D.; Sykulev, Yuri

doi:10.4049/jimmunol.1801196

Title: Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Abstract

MHC proteins that present peptide ligands for recognition by T-cell antigen receptor (TCR) form nano-scale clusters on the cell membrane of antigen-presenting cells. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nano-scale discoidal membrane mimetics (nanolipoprotein particles, or NLPs) to capture and present pMHC ligands at various densities. We examined the binding of these model membrane clusters to the surface of live CD8⁺ T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8-MHC interactions, and relatively long lifetime of cognate TCRpMHC complexes emerge as essential parameters explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggested a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T-cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate antigen recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T-cell responses.

Authors:

Anikeeva, Nadia ^[1]; Fischer, Nicholas O. ^[2]; Blanchette, Craig D. ^[2];

^[1]

Thomas Jefferson Univ., Philladelphia, PA (United States)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

Publication Date:: Mon Jan 07 00:00:00 EST 2019

Research Org.:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Org.:: USDOE National Nuclear Security Administration (NNSA)

OSTI Identifier:: 1497300

Report Number(s):: LLNL-JRNL-737703
Journal ID: ISSN 0022-1767; 890710

Grant/Contract Number:: AC52-07NA27344

Resource Type:: Accepted Manuscript

Journal Name:: Journal of Immunology

Additional Journal Information:: Journal Volume: 202; Journal Issue: 2; Journal ID: ISSN 0022-1767

Publisher:: The American Association of Immunologists, Inc.

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES

Citation Formats


                    Anikeeva, Nadia, Fischer, Nicholas O., Blanchette, Craig D., and Sykulev, Yuri. Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses.  United States: N. p., 2019. 
Web.  doi:10.4049/jimmunol.1801196.

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                    Anikeeva, Nadia, Fischer, Nicholas O., Blanchette, Craig D., & Sykulev, Yuri. Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses.  United States.  https://doi.org/10.4049/jimmunol.1801196

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                    Anikeeva, Nadia, Fischer, Nicholas O., Blanchette, Craig D., and Sykulev, Yuri. Mon .  
"Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses".  United States.  https://doi.org/10.4049/jimmunol.1801196.  https://www.osti.gov/servlets/purl/1497300.

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@article{osti_1497300,

  title        = {Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses},

  author       = {Anikeeva, Nadia and Fischer, Nicholas O. and Blanchette, Craig D. and Sykulev, Yuri},

  abstractNote = {MHC proteins that present peptide ligands for recognition by T-cell antigen receptor (TCR) form nano-scale clusters on the cell membrane of antigen-presenting cells. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nano-scale discoidal membrane mimetics (nanolipoprotein particles, or NLPs) to capture and present pMHC ligands at various densities. We examined the binding of these model membrane clusters to the surface of live CD8+ T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8-MHC interactions, and relatively long lifetime of cognate TCRpMHC complexes emerge as essential parameters explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggested a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T-cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate antigen recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T-cell responses.},

  doi          = {10.4049/jimmunol.1801196},

  journal      = {Journal of Immunology},

  number       = 2,

  volume       = 202,

  place        = {United States},

  year         = {Mon Jan 07 00:00:00 EST 2019},

  month        = {Mon Jan 07 00:00:00 EST 2019}

}

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Title: Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Abstract

Citation Formats

An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein. journal, December 1991

Trafficking of MHC molecules to the cell surface creates dynamic protein patches journal, July 2016

Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes journal, April 2005

Gene regulation mediated by calcium signals in T lymphocytes journal, April 2001

The major substrates for TAP in vivo are derived from newly synthesized proteins journal, April 2000

Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation journal, August 2000

T Cell Receptor Signaling Kinetics Takes the Stage journal, December 2010

T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state journal, October 2007

T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters journal, May 2011

The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens journal, October 1987

Domains in Cell Plasma Membranes Investigated by Near-Field Scanning Optical Microscopy journal, May 1998

Agonist/endogenous peptide–MHC heterodimers drive T cell activation and sensitivity journal, February 2005

Kinetic Control of Histidine-Tagged Protein Surface Density on Supported Lipid Bilayers journal, April 2008

Mechanisms controlling granule-mediated cytolytic activity of cytotoxic T lymphocytes journal, November 2011

Kinetics of Early T Cell Receptor Signaling Regulate the Pathway of Lytic Granule Delivery to the Secretory Domain journal, October 2009

Nonstimulatory peptides contribute to antigen-induced CD8–T cell receptor interaction at the immunological synapse journal, June 2005

High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease journal, June 1993

Conjugation to Nickel-Chelating Nanolipoprotein Particles Increases the Potency and Efficacy of Subunit Vaccines to Prevent West Nile Encephalitis journal, June 2010

CD8 Kinetically Promotes Ligand Binding to the T-Cell Antigen Receptor journal, September 2005

Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking journal, December 2013

Structure of the human class I histocompatibility antigen, HLA-A2 journal, October 1987

Distinct Molecular Mechanisms Account for the Specificity of Two Different T-Cell Receptors journal, April 2003

Exploring avidity: understanding the potential gains in functional affinity and target residence time of bivalent and heterobivalent ligands: Exploring bivalent ligand binding properties journal, March 2013

Two-Stage Cooperative T Cell Receptor-Peptide Major Histocompatibility Complex-CD8 Trimolecular Interactions Amplify Antigen Discrimination journal, January 2011

The T-cell receptor signalosome: a dynamic structure with expanding complexity journal, June 2002

Soluble HIV-specific T cell receptor: expression, purification and analysis of the specificity journal, June 2003

CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes journal, December 1996

NSOM/QD-Based Direct Visualization of CD3-Induced and CD28-Enhanced Nanospatial Coclustering of TCR and Coreceptor in Nanodomains in T Cell Activation journal, June 2009

Integrins Influence the Size and Dynamics of Signaling Microclusters in a Pyk2-dependent Manner journal, March 2015

Dynamic Patches of Membrane Proteins journal, September 2007

ICAM-1 co-stimulates target cells to facilitate antigen presentation journal, June 2005

Major histocompatibility complex class I-intercellular adhesion molecule-1 association on the surface of target cells: implications for antigen presentation to cytotoxic T lymphocytes journal, December 2004

Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2 journal, April 1987

Quantum dot/peptide-MHC biosensors reveal strong CD8-dependent cooperation between self and viral antigens that augment the T cell response journal, October 2006

Evidence that the Density of Self Peptide-MHC Ligands Regulates T-Cell Receptor Signaling journal, August 2012

Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy journal, April 1996

Altered TCR Signaling from Geometrically Repatterned Immunological Synapses journal, November 2005

Changing separating distances between immune receptors as a sensitive mechanism regulating T cell activation journal, January 2010

Characterization and Purification of Polydisperse Reconstituted Lipoproteins and Nanolipoprotein Particles journal, July 2009

Immobilization of His-Tagged Proteins on Nickel-Chelating Nanolipoprotein Particles journal, March 2009

Kinetic Analysis of His-Tagged Protein Binding to Nickel-Chelating Nanolipoprotein Particles journal, July 2010

Enhancement of antigen-specific CD4+ and CD8+ T cell responses using a self-assembled biologic nanolipoprotein particle vaccine journal, March 2017

Proximity of TCR and its CD8 coreceptor controls sensitivity of T cells journal, January 2014

An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein.
journal, December 1991

Trafficking of MHC molecules to the cell surface creates dynamic protein patches
journal, July 2016

Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes
journal, April 2005

Gene regulation mediated by calcium signals in T lymphocytes
journal, April 2001

The major substrates for TAP in vivo are derived from newly synthesized proteins
journal, April 2000

Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation
journal, August 2000

T Cell Receptor Signaling Kinetics Takes the Stage
journal, December 2010

T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state
journal, October 2007

T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters
journal, May 2011

The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens
journal, October 1987

Domains in Cell Plasma Membranes Investigated by Near-Field Scanning Optical Microscopy
journal, May 1998

Agonist/endogenous peptide–MHC heterodimers drive T cell activation and sensitivity
journal, February 2005

Kinetic Control of Histidine-Tagged Protein Surface Density on Supported Lipid Bilayers
journal, April 2008

Mechanisms controlling granule-mediated cytolytic activity of cytotoxic T lymphocytes
journal, November 2011

Kinetics of Early T Cell Receptor Signaling Regulate the Pathway of Lytic Granule Delivery to the Secretory Domain
journal, October 2009

Nonstimulatory peptides contribute to antigen-induced CD8–T cell receptor interaction at the immunological synapse
journal, June 2005

High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease
journal, June 1993

Conjugation to Nickel-Chelating Nanolipoprotein Particles Increases the Potency and Efficacy of Subunit Vaccines to Prevent West Nile Encephalitis
journal, June 2010

CD8 Kinetically Promotes Ligand Binding to the T-Cell Antigen Receptor
journal, September 2005

Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking
journal, December 2013

Structure of the human class I histocompatibility antigen, HLA-A2
journal, October 1987

Distinct Molecular Mechanisms Account for the Specificity of Two Different T-Cell Receptors
journal, April 2003

Exploring avidity: understanding the potential gains in functional affinity and target residence time of bivalent and heterobivalent ligands: Exploring bivalent ligand binding properties
journal, March 2013

Two-Stage Cooperative T Cell Receptor-Peptide Major Histocompatibility Complex-CD8 Trimolecular Interactions Amplify Antigen Discrimination
journal, January 2011

The T-cell receptor signalosome: a dynamic structure with expanding complexity
journal, June 2002

Soluble HIV-specific T cell receptor: expression, purification and analysis of the specificity
journal, June 2003

CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes
journal, December 1996

NSOM/QD-Based Direct Visualization of CD3-Induced and CD28-Enhanced Nanospatial Coclustering of TCR and Coreceptor in Nanodomains in T Cell Activation
journal, June 2009

Integrins Influence the Size and Dynamics of Signaling Microclusters in a Pyk2-dependent Manner
journal, March 2015

Dynamic Patches of Membrane Proteins
journal, September 2007

ICAM-1 co-stimulates target cells to facilitate antigen presentation
journal, June 2005

Major histocompatibility complex class I-intercellular adhesion molecule-1 association on the surface of target cells: implications for antigen presentation to cytotoxic T lymphocytes
journal, December 2004

Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2
journal, April 1987

Quantum dot/peptide-MHC biosensors reveal strong CD8-dependent cooperation between self and viral antigens that augment the T cell response
journal, October 2006

Evidence that the Density of Self Peptide-MHC Ligands Regulates T-Cell Receptor Signaling
journal, August 2012

Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy
journal, April 1996

Altered TCR Signaling from Geometrically Repatterned Immunological Synapses
journal, November 2005

Changing separating distances between immune receptors as a sensitive mechanism regulating T cell activation
journal, January 2010

Characterization and Purification of Polydisperse Reconstituted Lipoproteins and Nanolipoprotein Particles
journal, July 2009

Immobilization of His-Tagged Proteins on Nickel-Chelating Nanolipoprotein Particles
journal, March 2009

Kinetic Analysis of His-Tagged Protein Binding to Nickel-Chelating Nanolipoprotein Particles
journal, July 2010

Enhancement of antigen-specific CD4+ and CD8+ T cell responses using a self-assembled biologic nanolipoprotein particle vaccine
journal, March 2017

Proximity of TCR and its CD8 coreceptor controls sensitivity of T cells
journal, January 2014