A Journey to the Conformational Analysis of T-Cell Epitope Peptides Involved in Multiple Sclerosis

Multiple sclerosis (MS) is a serious central nervous system (CNS) disease responsible for disability problems and deterioration of the quality of life. Several approaches have been applied to medications entering the market to treat this disease. However, no effective therapy currently exists, and the available drugs simply ameliorate the destructive disability effects of the disease. In this review article, we report on the efforts that have been conducted towards establishing the conformational properties of wild-type myelin basic protein (MBP), myelin proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) epitopes or altered peptide ligands (ALPs). These efforts have led to the aim of discovering some non-peptide mimetics possessing considerable activity against the disease. These efforts have contributed also to unveiling the molecular basis of the molecular interactions implicated in the trimolecular complex, T-cell receptor (TCR)–peptide–major histocompatibility complex (MHC) or human leucocyte antigen (HLA).

Download Full-text

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

10.1101/2020.09.23.310375 ◽

2020 ◽

Author(s):

Mathew Clement ◽

Lea Knezevic ◽

Tamsin Dockree ◽

James E. McLaren ◽

Kristin Ladell ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Theoretical Models ◽

Cell Receptor ◽

Dissociation Rate ◽

Peptide Ligands ◽

Controlled System ◽

Peptide Antigens ◽

Histocompatibility Complex ◽

The Relationship

ABSTRACTCD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used an intrinsically controlled system to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.SIGNIFICANCESufficient immune coverage of the peptide universe within a finite host requires highly degenerate T cell receptors (TCRs). However, this inherent need for antigen cross-recognition is associated with a high risk of autoimmunity, which can only be mitigated by a process of adaptable specificity. We describe a mechanism that resolves this conundrum by allowing individual clonotypes to focus on specific peptide ligands without alterations to the structure of the TCR.

Download Full-text

Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands.

Journal of Experimental Medicine ◽

10.1084/jem.184.4.1259 ◽

1996 ◽

Vol 184 (4) ◽

pp. 1259-1268 ◽

Cited By ~ 132

Author(s):

G J Kersh ◽

P M Allen

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Clone ◽

Cell Receptor ◽

Peptide Ligands ◽

Structural Basis ◽

Side Chain ◽

Contact Residue ◽

Altered Peptide Ligands ◽

T Cell Clone

T cells recognize short linear peptides bound to major histocompatibility complex (MHC)-encoded molecules. Subtle molecular changes in peptide antigens produce altered peptide ligands (APLs), which induce different T cell responses from those induced by the antigenic ligand. A molecular basis for how these slight molecular variations lead to such different consequences for the T cell has not been described. To address this issue, we have made amino acid substitutions at the primary T cell receptor (TCR) contact residue of the murine hemoglobin determinant, Hb(64-76)/I-Ek and produced 12 peptides that interact with the TCR of the T cell clone 3.L2. The 3.L2 T cell responds to these peptides, which vary 1 million-fold in their activity, and enables them to be ranked according to their relative ability to signal through the 3.L2 TCR. Such a ranking reveals that the ability of the 3.L2 T cell to respond to these peptides depends on how well the structure of the side chain at the primary TCR contact site mimics that of the Asn residue present in the antigenic ligand. The reactivity of the 3.L2 T cell also depends on an MHC contact residue that is next to the primary TCR contact residue, suggesting that conformation of the Asn side chain is also important. By using nonnatural amino acids at a TCR contact residue, we have demonstrated that APLs can be rationally designed based on structure. These data are consistent with a model in which the affinity of a peptide-MHC complex for the TCR determines how the T cell will respond.

Download Full-text

Early Relaxation Dynamics in the LC 13 T Cell Receptor in Reaction to 172 Altered Peptide Ligands: A Molecular Dynamics Simulation Study

PLoS ONE ◽

10.1371/journal.pone.0064464 ◽

2013 ◽

Vol 8 (6) ◽

pp. e64464 ◽

Cited By ~ 10

Author(s):

Bernhard Knapp ◽

Georg Dorffner ◽

Wolfgang Schreiner

Keyword(s):

Molecular Dynamics ◽

T Cell ◽

Molecular Dynamics Simulation ◽

T Cell Receptor ◽

Simulation Study ◽

Cell Receptor ◽

Peptide Ligands ◽

Dynamics Simulation ◽

Relaxation Dynamics ◽

Altered Peptide Ligands

Download Full-text

Comparison of Proposed Putative Active Conformations of Myelin Basic Protein Epitope 87−99 Linear Altered Peptide Ligands by Spectroscopic and Modelling Studies: The Role of Positions 91 and 96 in T-Cell Receptor Activation

Journal of Medicinal Chemistry ◽

10.1021/jm060040z ◽

2006 ◽

Vol 49 (23) ◽

pp. 6683-6691 ◽

Cited By ~ 17

Author(s):

Efthimia D. Mantzourani ◽

Theodore V. Tselios ◽

Simona Golic Grdadolnik ◽

James A. Platts ◽

Andrea Brancale ◽

...

Keyword(s):

T Cell ◽

Myelin Basic Protein ◽

T Cell Receptor ◽

Basic Protein ◽

Cell Receptor ◽

Receptor Activation ◽

Peptide Ligands ◽

Altered Peptide Ligands ◽

Modelling Studies

Download Full-text

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2019639118 ◽

2021 ◽

Vol 118 (29) ◽

pp. e2019639118

Author(s):

Mathew Clement ◽

Lea Knezevic ◽

Tamsin Dockree ◽

James E. McLaren ◽

Kristin Ladell ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Theoretical Models ◽

Cell Receptor ◽

Dissociation Rate ◽

Peptide Ligands ◽

Peptide Antigens ◽

Controlled Systems ◽

Histocompatibility Complex ◽

The Relationship

CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.

Download Full-text

Rapid selection and identification of functional CD8+ T cell epitopes from large peptide-coding libraries

Nature Communications ◽

10.1038/s41467-019-12444-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Govinda Sharma ◽

Craig M. Rive ◽

Robert A. Holt

Keyword(s):

T Cells ◽

T Cell ◽

Cell Epitope ◽

Cell Receptor ◽

T Cell Response ◽

Target Cells ◽

T Cell Epitopes ◽

Peptide Epitopes ◽

Histocompatibility Complex

Abstract Cytotoxic CD8+ T cells recognize and eliminate infected or malignant cells that present peptide epitopes derived from intracellularly processed antigens on their surface. However, comprehensive profiling of specific major histocompatibility complex (MHC)-bound peptide epitopes that are naturally processed and capable of eliciting a functional T cell response has been challenging. Here, we report a method for deep and unbiased T cell epitope profiling, using in vitro co-culture of CD8+ T cells together with target cells transduced with high-complexity, epitope-encoding minigene libraries. Target cells that are subject to cytotoxic attack from T cells in co-culture are isolated prior to apoptosis by fluorescence-activated cell sorting, and characterized by sequencing the encoded minigenes. We then validate this highly parallelized method using known murine T cell receptor/peptide-MHC pairs and diverse minigene-encoded epitope libraries. Our data thus suggest that this epitope profiling method allows unambiguous and sensitive identification of naturally processed and MHC-presented peptide epitopes.

Download Full-text

Altered Peptide Ligands Induce Delayed CD8-T Cell Receptor Interaction—a Role for CD8 in Distinguishing Antigen Quality

Immunity ◽

10.1016/j.immuni.2006.05.015 ◽

2006 ◽

Vol 25 (2) ◽

pp. 203-211 ◽

Cited By ~ 70

Author(s):

Pia P. Yachi ◽

Jeanette Ampudia ◽

Tomasz Zal ◽

Nicholas R.J. Gascoigne

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cd8 T Cell ◽

Cell Receptor ◽

Peptide Ligands ◽

Receptor Interaction ◽

Altered Peptide Ligands

Download Full-text

Selective activation of the calcium signaling pathway by altered peptide ligands.

Journal of Experimental Medicine ◽

10.1084/jem.184.4.1525 ◽

1996 ◽

Vol 184 (4) ◽

pp. 1525-1530 ◽

Cited By ~ 56

Author(s):

J Sloan-Lancaster ◽

T H Steinberg ◽

P M Allen

Keyword(s):

T Cells ◽

T Cell ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Direct Consequence ◽

Cell Receptor ◽

Cytosolic Calcium ◽

Peptide Ligands ◽

Altered Peptide Ligands ◽

T Cell Anergy

We previously demonstrated that altered peptide ligands (APL) can partially activate T cells, resulting in multiple distinct functional phenotypes, including the induction of anergy. Such APL stimulate a unique pattern of T cell receptor (TCR) phospho-zeta species, and lack associated ZAP-70 kinase activity. While these data suggested that selective signaling pathways downstream of the TCR/CD3 molecules are activated upon APL stimulation, they did not directly demonstrate this. Thus, we pursued intracellular signaling events successfully stimulated by APL. Because our previous studies showed that cyclosporin A (CsA) completely inhibited anergy induction, we assessed whether TCR ligation by APL cause a rise in cytosolic calcium (Ca+2). Our results show that these ligands can induce Ca+2 transients, in contrast to data generated using analogue peptides in other antigen systems. These opposing results may reflect differences in the intracellular signaling pathways utilized by different APL, or may be due to the exquisite sensitivity of the assay used here. Importantly, the APL-stimulated Ca+2 induction is both initiated and sustained at lower levels than that stimulated by a strong agonist signal, but resembles that stimulated by a weaker agonist stimulus. Alone, the less than optimal Ca+2 induction does not cause anergy, because ionomycin treatment together with the APL does not result in a proliferative signal. Instead, we propose that a combination of this and other signaling pathways induces T cell anergy. Overall, these data support the concept of differential signaling in T cells, as a direct consequence of the phosphotyrosine status of the TCR/CD3 molecules.

Download Full-text