scholarly journals How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

2008 ◽  
Vol 28 (12) ◽  
pp. 4040-4051 ◽  
Author(s):  
Huan Zheng ◽  
Bo Jin ◽  
Sarah E. Henrickson ◽  
Alan S. Perelson ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Antigen Dose ◽  
Binding Characteristics ◽  
Mhc Genes ◽  
Antigenic Proteins ◽  
Future Experimentation ◽  
Time Required ◽  
Antigen Presenting

ABSTRACT T lymphocytes (T cells) express T-cell receptor (TCR) molecules on their surface that can recognize peptides (p) derived from antigenic proteins bound to products of the major histocompatibility complex (MHC) genes. The pMHC molecules are expressed on the surface of antigen-presenting cells, such as dendritic cells (DCs). T cells first encounter antigen on DCs in lymph nodes (LN). Intravital microscopy experiments show that upon entering the LN containing antigen, CD8+ T cells first move rapidly. After a few hours, they stop and make extended contacts with DCs. The factors that determine when and how this transition occurs are not well understood. We report results from computer simulations that suggest that the duration of phase one is related to the low probability of productive interactions between T cells and DCs. This is demonstrated by our finding that the antigen dose and type determine when such a transition occurs. These results are in agreement with experimental observations. TCR-pMHC binding characteristics and the antigen dose determine the time required for a productive T-cell-DC encounter (resulting in sustained contact). We find that the ratio of this time scale and the half-life of the pMHC complex itself provide a consolidated measure of antigen quantity and type. Results obtained upon varying different measures of antigen quantity and type fall on one curve when graphed against this ratio of time scales. Thus, we provide a mechanism for how the effects of varying one set of parameters are influenced by other prevailing conditions. This understanding should help guide future experimentation.

scholarly journals Restricting nonclassical MHC genes coevolve with TRAV genes used by innate-like T cells in mammals

2016 ◽  
Vol 113 (21) ◽  
pp. E2983-E2992 ◽  
Author(s):  
Pierre Boudinot ◽  
Stanislas Mondot ◽  
Luc Jouneau ◽  
Luc Teyton ◽  
Marie-Paule Lefranc ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Purifying Selection ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Evolutionary Patterns ◽  
Mait Cells ◽  
Mhc Genes ◽  
Class 1 ◽  
Complementarity Determining Regions

Whereas major histocompatibility class-1 (MH1) proteins present peptides to T cells displaying a large T-cell receptor (TR) repertoire, MH1Like proteins, such as CD1D and MR1, present glycolipids and microbial riboflavin precursor derivatives, respectively, to T cells expressing invariant TR-α (iTRA) chains. The groove of such MH1Like, as well as iTRA chains used by mucosal-associated invariant T (MAIT) and natural killer T (NKT) cells, respectively, may result from a coevolution under particular selection pressures. Herein, we investigated the evolutionary patterns of the iTRA of MAIT and NKT cells and restricting MH1Like proteins: MR1 appeared 170 Mya and is highly conserved across mammals, evolving more slowly than other MH1Like. It has been pseudogenized or independently lost three times in carnivores, the armadillo, and lagomorphs. The corresponding TRAV1 gene also evolved slowly and harbors highly conserved complementarity determining regions 1 and 2. TRAV1 is absent exclusively from species in which MR1 is lacking, suggesting that its loss released the purifying selection on MR1. In the rabbit, which has very few NKT and no MAIT cells, a previously unrecognized iTRA was identified by sequencing leukocyte RNA. This iTRA uses TRAV41, which is highly conserved across several groups of mammals. A rabbit MH1Like gene was found that appeared with mammals and is highly conserved. It was independently lost in a few groups in which MR1 is present, like primates and Muridae, illustrating compensatory emergences of new MH1Like/Invariant T-cell combinations during evolution. Deciphering their role is warranted to search similar effector functions in humans.

scholarly journals Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

2017 ◽  
Vol 214 (11) ◽  
pp. 3417-3433 ◽  
Author(s):  
Xiaojing Chen ◽  
Lucia Poncette ◽  
Thomas Blankenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Mhc Molecules ◽  
Mhc Ii ◽  
Cdr3 Length ◽  
Tcr Repertoire ◽  
Cell Diversity ◽  
Antigen Presenting

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

scholarly journals Small amounts of superantigen, when presented on dendritic cells, are sufficient to initiate T cell responses.

1993 ◽  
Vol 178 (2) ◽  
pp. 633-642 ◽  
Author(s):  
N Bhardwaj ◽  
J W Young ◽  
A J Nisanian ◽  
J Baggers ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
Cell Mediated Immunity ◽  
Quiescent T Cells ◽  
Antigen Presenting

Dendritic cells are potent antigen-presenting cells for several primary immune responses and therefore provide an opportunity for evaluating the amounts of cell-associated antigens that are required for inducing T cell-mediated immunity. Because dendritic cells express very high levels of major histocompatibility complex (MHC) class II products, it has been assumed that high levels of ligands bound to MHC products ("signal one") are needed to stimulate quiescent T cells. Here we describe quantitative aspects underlying the stimulation of human blood T cells by a bacterial superantigen, staphylococcal enterotoxin A (SEA). The advantages of superantigens for quantitative studies of signal one are that these ligands: (a) engage MHC class II and the T cell receptor but do not require processing; (b) are efficiently presented to large numbers of quiescent T cells; and (c) can be pulsed onto dendritic cells before their application to T cells. Thus one can relate amounts of dendritic cell-associated SEA to subsequent lymphocyte stimulation. Using radioiodinated SEA, we noted that dendritic cells can bind 30-200 times more superantigen than B cells and monocytes. Nevertheless, this high SEA binding does not underlie the strong potency of dendritic cells to present antigen to T cells. Dendritic cells can sensitize quiescent T cells, isolated using monoclonals to appropriate CD45R epitopes, after a pulse of SEA that occupies a maximum of 0.1% of surface MHC class II molecules. This corresponds to an average of 2,000 molecules per dendritic cell. At these low doses of bound SEA, monoclonal antibodies to CD3, CD4, and CD28 almost completely block T cell proliferation. In addition to suggesting new roles for MHC class II on dendritic cells, especially the capture and retention of ligands at low external concentrations, the data reveal that primary T cells can generate a response to exceptionally low levels of signal one as long as these are delivered on dendritic cells.

scholarly journals Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Pavel V. Shelyakin ◽  
Ksenia R. Lupyr ◽  
Evgeny S. Egorov ◽  
Ilya A. Kofiadi ◽  
Dmitriy B. Staroverov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cell Compartments ◽  
Expression Of Genes ◽  
Tcr Repertoire ◽  
Antigen Presenting

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

scholarly journals CD1: From Molecules to Diseases

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1909 ◽  
Author(s):  
D. Branch Moody ◽  
Sara Suliman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
High Genetic Diversity ◽  
Disease States ◽  
New Research ◽  
Antigen Presenting ◽  
Cluster Of Differentiation

The human cluster of differentiation (CD)1 system for antigen display is comprised of four types of antigen-presenting molecules, each with a distinct functional niche: CD1a, CD1b, CD1c, and CD1d. Whereas CD1 proteins were thought solely to influence T-cell responses through display of amphipathic lipids, recent studies emphasize the role of direct contacts between the T-cell receptor and CD1 itself. Moving from molecules to diseases, new research approaches emphasize human CD1-transgenic mouse models and the study of human polyclonal T cells in vivo or ex vivo in disease states. Whereas the high genetic diversity of major histocompatibility complex (MHC)-encoded antigen-presenting molecules provides a major hurdle for designing antigens that activate T cells in all humans, the simple population genetics of the CD1 system offers the prospect of discovering or designing broadly acting immunomodulatory agents.

scholarly journals Fyn-Binding Protein (Fyb)/Slp-76–Associated Protein (Slap), Ena/Vasodilator-Stimulated Phosphoprotein (Vasp) Proteins and the Arp2/3 Complex Link T Cell Receptor (Tcr) Signaling to the Actin Cytoskeleton

2000 ◽  
Vol 149 (1) ◽  
pp. 181-194 ◽  
Author(s):  
Matthias Krause ◽  
Antonio S. Sechi ◽  
Marlies Konradt ◽  
David Monner ◽  
Frank B. Gertler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Antigen Presenting ◽  
Syndrome Protein

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76–associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3–coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

scholarly journals Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 696 ◽  
Author(s):  
Bianca Simon ◽  
Dennis C. Harrer ◽  
Beatrice Schuler-Thurner ◽  
Gerold Schuler ◽  
Ugur Uslu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Dna And Rna ◽  
Antigen Loss ◽  
Antigen Presenting

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.

scholarly journals Interleukin-7 Enhances Proliferation Responses to T-Cell Receptor Stimulation in Naïve CD4+ T Cells from Human Immunodeficiency Virus-Infected Persons

2007 ◽  
Vol 81 (22) ◽  
pp. 12670-12674 ◽  
Author(s):  
Douglas A. Bazdar ◽  
Scott F. Sieg
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Healthy Controls ◽  
Receptor Stimulation ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Antigen Presenting

ABSTRACT Proliferation responses of naïve CD4+ T cells to T-cell receptor and interleukin-7 (IL-7) stimulation were evaluated by using cells from human immunodeficiency virus-positive (HIV+) donors. IL-7 enhanced responses to T-cell receptor stimulation, and the magnitude of this enhancement was similar in cells from healthy controls and from HIV+ subjects. The overall response to T-cell receptor stimulation alone or in combination with IL-7, however, was diminished among viremic HIV+ donors and occurred independent of antigen-presenting cells. Frequencies of CD127+ cells were related to the magnitudes of proliferation enhancement that were mediated by IL-7. Thus, IL-7 enhances but does not fully restore the function of naïve CD4+ T cells from HIV-infected persons.

scholarly journals RIAM Links the ADAP/SKAP-55 Signaling Module to Rap1, Facilitating T-Cell-Receptor-Mediated Integrin Activation

2007 ◽  
Vol 27 (11) ◽  
pp. 4070-4081 ◽  
Author(s):  
Gaël Ménasché ◽  
Stefanie Kliche ◽  
Emily J. H. Chen ◽  
Theresia E. B. Stradal ◽  
Burkhart Schraven ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Small Gtpase ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Integrin Activation ◽  
Tcr Signaling ◽  
Antigen Presenting

ABSTRACT One outcome of T-cell receptor (TCR) signaling is increased affinity and avidity of integrins for their ligands. This occurs through a process known as inside-out signaling, which has been shown to require several molecular components including the adapter proteins ADAP (adhesion and degranulation-promoting adapter protein) and SKAP-55 (55-kDa src kinase-associated phosphoprotein) and the small GTPase Rap1. Herein, we provide evidence linking ADAP and SKAP-55 to RIAM, a recently described adapter protein that binds selectively to active Rap1. We identified RIAM as a key component linking the ADAP/SKAP-55 module to the small GTPase Rap1, facilitating TCR-mediated integrin activation. We show that RIAM constitutively interacts with SKAP-55 in both a heterologous transfection system and primary T cells and map the region essential for this interaction. Additionally, we find that the SKAP-55/RIAM complex is essential both for TCR-mediated adhesion and for efficient conjugate formation between T cells and antigen-presenting cells. Mechanistic studies revealed that the ADAP/SKAP-55 module relocalized RIAM and Rap1 to the plasma membrane following TCR activation to facilitate integrin activation. These results describe for the first time a link between ADAP/SKAP-55 and the Rap1/RIAM complex and provide a potential new mechanism for TCR-mediated integrin activation.

scholarly journals Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination

2017 ◽  
Vol 114 (46) ◽  
pp. 12190-12195 ◽  
Author(s):  
Rafal M. Pielak ◽  
Geoff P. O’Donoghue ◽  
Jenny J. Lin ◽  
Katherine N. Alfieri ◽  
Nicole C. Fay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Single Molecule ◽  
Cell Activation ◽  
Cell Receptor ◽  
Physical Constraints ◽  
Molecular Binding ◽  
Antigen Presenting

Antigen discrimination by T cells occurs at the junction between a T cell and an antigen-presenting cell. Juxtacrine binding between numerous adhesion, signaling, and costimulatory molecules defines both the topographical and lateral geometry of this cell–cell interface, within which T cell receptor (TCR) and peptide major histocompatibility complex (pMHC) interact. These physical constraints on receptor and ligand movement have significant potential to modulate their molecular binding properties. Here, we monitor individual ligand:receptor binding and unbinding events in space and time by single-molecule imaging in live primary T cells for a range of different pMHC ligands and surface densities. Direct observations of pMHC:TCR and CD80:CD28 binding events reveal that the in situ affinity of both pMHC and CD80 ligands for their respective receptors is modulated by the steady-state number of agonist pMHC:TCR interactions experienced by the cell. By resolving every single pMHC:TCR interaction it is evident that this cooperativity is accomplished by increasing the kinetic on-rate without altering the off-rate and has a component that is not spatially localized. Furthermore, positive cooperativity is observed under conditions where the T cell activation probability is low. This TCR-mediated feedback is a global effect on the intercellular junction. It is triggered by the first few individual pMHC:TCR binding events and effectively increases the efficiency of TCR scanning for antigen before the T cell is committed to activation.

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