scholarly journals Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response against the AH1 tumor rejection antigen

2019 ◽  
Author(s):  
Philipp Probst ◽  
Marco Stringhini ◽  
Dario Neri
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Leukemia Virus ◽  
Cell Receptor ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Tumor Mass ◽  
Tumor Rejection Antigen ◽  
Immunocompetent Mice

AbstractThe possibility to cure immunocompetent mice bearing murine CT26 colorectal tumors using cytokine-based therapeutics allows to study the tumor rejection process at a molecular level. Following treatment with L19-mIL12 or F8-mTNF, two antibody fusion proteins which preferentially concentrate a murine cytokine payload at the tumor site, CT26 tumors could be cured in a process that crucially relies on CD8+ T cells. In both settings, the AH1 peptide (derived from the gp70 envelop protein of murine leukemia virus) acted as the main tumor rejection antigen and ~50% of CD8+ T cells in the tumor mass are AH1-specific after therapy. In order to characterize the clonality of the T cell response after successful antibody-cytokine immunotherapy, we isolated CD8+ T cells from tumors and submitted them to T cell receptor (TCR) sequencing. As expected, different TCR sequences were found in different mice, as these molecules originate from a stochastic rearrangement process. CD8+ T cells featuring the ten most abundant TCR sequences represented more than 60% of total CD8+ T cell clones in the tumor mass, but less than 10% in the spleen. Looking at sorted CD8+ T cells from individual animals, AH1-specific TCRs were consistently found among the most abundant sequences. Collectively, these data suggest that the antitumor response driven by two different antibody-cytokine fusions proceeds through an oligoclonal expansion and activation of tumor-infiltrating CD8+ T cells.

Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2244-2253 ◽  
Author(s):  
Michael Rist ◽  
Corey Smith ◽  
Melissa J. Bell ◽  
Scott R. Burrows ◽  
Rajiv Khanna
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Allograft Rejection ◽  
Functional Characterization ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Repertoire ◽  
Diverse Range

Abstract The ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.

scholarly journals Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1922
Author(s):  
Julia Peña-Asensio ◽  
Henar Calvo ◽  
Miguel Torralba ◽  
Joaquín Miquel ◽  
Eduardo Sanz-de-Villalobos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
T Cell Response ◽  
Immune Checkpoints ◽  
Tumor Resistance ◽  
Cell Reactivity ◽  
Precursor Pool ◽  
Cd8 Cells

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.

scholarly journals Clonally expanded virus-specific CD8 T cells acquire diverse transcriptional phenotypes during acute, chronic, and latent infections

2021 ◽  
Author(s):  
Raphael Kuhn ◽  
Ioana Sandu ◽  
Andreas Agrafiotis ◽  
Kai-Lin Hong ◽  
Daniel Neumeier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Clonal Selection ◽  
Acute Infection ◽  
Cell Receptor ◽  
T Cell Response ◽  
Wide Range ◽  
Infection Types

CD8+ T cells play a crucial role in the control and resolution of viral infections and can adopt a wide range of phenotypes and effector functions depending on the inflammatory context and the duration and extent of antigen exposure. Similarly, viral infections can exert diverse selective pressures on populations of clonally related T cells. Technical limitations have nevertheless made it challenging to investigate the relationship between clonal selection and transcriptional phenotypes of virus-specific T cells. We therefore performed single-cell T cell receptor (TCR) repertoire and transcriptome sequencing of virus-specific CD8 T cells in murine models of acute, chronic and latent infection. We observed clear infection-specific populations corresponding to memory, effector, exhausted, and inflationary phenotypes. We further uncovered a mouse-specific and polyclonal T cell response, despite all T cells sharing specificity to a single viral epitope, which was accompanied by stereotypic TCR germline gene usage in all three infection types. Persistent antigen exposure during chronic and latent viral infections resulted in a higher proportion of clonally expanded T cells relative to acute infection. We furthermore observed a relationship between transcriptional heterogeneity and clonal expansion for all three infections, with highly expanded clones having distinct transcriptional phenotypes relative to lowly expanded clones. Finally, we developed and utilized a bioinformatic pipeline integrating pseudotime and clonality, termed Clonotyme, to further support a model in which expanded virus-specific CD8+ T cells adopt heterogenic, yet preferentially, effector-like phenotypes. Together our work relates clonal selection to gene expression in the context of viral infection and further provides a dataset and accompanying software for the immunological community.

scholarly journals In chronic infection, HIV gag-specific CD4+ T cell receptor diversity is higher than CD8+ T cell receptor diversity and is associated with less HIV quasispecies diversity

2021 ◽  
Author(s):  
Mark A Pilkinton ◽  
Wyatt J McDonnell ◽  
Louise Barnett ◽  
Abha Chopra ◽  
Rama Gangula ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Tcr Repertoire ◽  
Tcr Diversity

Cellular immune responses to Gag correlate with improved HIV viral control. The full extent of cellular immune responses comprise both the number of epitopes recognized by CD4+ and CD8+ T cells, as well as the diversity of the T cell receptor (TCR) repertoire directed against each epitope. The optimal diversity of the responsive TCR repertoire is unclear. Therefore, we evaluated the TCR diversity of CD4+ and CD8+ T cells responding to HIV-1 Gag to determine if TCR diversity correlates with clinical or virologic metrics. Previous studies of TCR repertoires have been limited primarily to CD8+ T cell responses directed against a small number of well-characterized T cell epitopes restricted by specific human leucocyte antigens. We stimulated peripheral blood mononuclear cells from 21chronic HIV-infected individuals overnight with a pool of HIV-1 Gag peptides, followed by sorting of activated CD4+ and CD8+ T cells and TCR deep sequencing. We found Gag-reactive CD8+ T cells to be more oligoclonal, with a few dominant TCRs comprising the bulk of the repertoire, compared to the highly diverse TCR repertoires of Gag-reactive CD4+ T cells. HIV viral sequencing of the same donors revealed that high CD4+ T cell TCR diversity was strongly associated with lower HIV Gag genetic diversity. We conclude that the TCR repertoire of Gag-reactive CD4+ T helper cells display substantial diversity without a clearly dominant circulating TCR clonotype, in contrast to a hierarchy of dominant TCR clonotypes in the Gag-reactive CD8+ T cells, and may serve to limit HIV diversity during chronic infection. IMPORTANCE Human T cells recognize portions of viral proteins bound to host molecules (human leucocyte antigens) on the surface of infected cells. T cells recognize these foreign proteins through their T cell receptors (TCRs), which are formed by the assortment of several available V, D and J genes to create millions of combinations of unique TCRs. We measured the diversity of T cells responding to the HIV Gag protein. We found the CD8+ T cell response is primarily made up of a few dominant unique TCRs whereas the CD4+ T cell subset has a much more diverse repertoire of TCRs. We also found there was less change in the virus sequences in subjects with more diverse TCR repertoires. HIV has a high mutation rate, which allows it to evade the immune response. Our findings describe the characteristics of a virus-specific T cell response that may allow it to limit viral evolution.

scholarly journals PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells

2004 ◽  
Vol 64 (3) ◽  
pp. 1140-1145 ◽  
Author(s):  
Christian Blank ◽  
Ian Brown ◽  
Amy C. Peterson ◽  
Mike Spiotto ◽  
Yoshiko Iwai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Tumor Rejection ◽  
Effector Phase

scholarly journals Human fetuses are able to mount an adultlike CD8 T-cell response

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2153-2158 ◽  
Author(s):  
Emmanuel Hermann ◽  
Carine Truyens ◽  
Cristina Alonso-Vega ◽  
Jos Even ◽  
Patricia Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Interferon Γ ◽  
T Cell Response ◽  
Activation Markers ◽  
T Cell Receptor Beta

Abstract Fetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.

scholarly journals Human fetuses are able to mount an adultlike CD8 T-cell response

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2153-2158
Author(s):  
Emmanuel Hermann ◽  
Carine Truyens ◽  
Cristina Alonso-Vega ◽  
Jos Even ◽  
Patricia Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Interferon Γ ◽  
T Cell Response ◽  
Activation Markers ◽  
T Cell Receptor Beta

Fetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.

scholarly journals T-cell receptor V? gene usage by T cells reactive with the tumor-rejection antigen SART-1 in oral squamous cell carcinoma

2003 ◽  
Vol 108 (5) ◽  
pp. 686-695 ◽  
Author(s):  
Wataru Kumamaru ◽  
Seiji Nakamura ◽  
Tsutomu Kadena ◽  
Akira Yamada ◽  
Eiji Kawamura ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Oral Squamous Cell Carcinoma ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Tumor Rejection ◽  
Tumor Rejection Antigen ◽  
Gene Usage ◽  
V Gene

scholarly journals Analysis of TCR Repertoire by High-Throughput Sequencing Indicates the Feature of T Cell Immune Response after SARS-CoV-2 Infection

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 68
Author(s):  
Yifan Wang ◽  
Fugang Duan ◽  
Zhu Zhu ◽  
Meng Yu ◽  
Xiaodong Jia ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
T Cell Response ◽  
Patient Specific ◽  
Cell Immune Response ◽  
Tcr Repertoire

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by the SARS-CoV-2 coronavirus. T cells play an essential role in the body’s fighting against the virus invasion, and the T cell receptor (TCR) is crucial in T cell-mediated virus recognition and clearance. However, little has been known about the features of T cell response in convalescent COVID-19 patients. In this study, using 5′RACE technology and PacBio sequencing, we analyzed the TCR repertoire of COVID-19 patients after recovery for 2 weeks and 6 months compared with the healthy donors. The TCR clustering and CDR3 annotation were exploited to discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. We first identified CD4+ and CD8+ T cell clones with certain clonal expansion after infection, and then observed the preferential recombination usage of V(D) J gene segments in CD4+ and CD8+ T cells of COVID-19 patients with different convalescent stages. More important, the TRBV6-5-TRBD2-TRBJ2-7 combination with high frequency was shared between CD4+ T and CD8+ T cells of different COVID-19 patients. Finally, we found the dominant characteristic motifs of the CDR3 sequence between recovered COVID-19 and healthy control. Our study provides novel insights on TCR in COVID-19 with different convalescent phases, contributing to our understanding of the immune response induced by SARS-CoV-2.

scholarly journals Tumor Rejection Induced by CD70-mediated Quantitative and Qualitative Effects on Effector CD8+ T Cell Formation

2004 ◽  
Vol 199 (11) ◽  
pp. 1595-1605 ◽  
Author(s):  
Ramon Arens ◽  
Koen Schepers ◽  
Martijn A. Nolte ◽  
Michiel F. van Oosterwijk ◽  
René A.W. van Lier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Formation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Dependent Manner ◽  
Ifn Γ

In vivo priming of antigen-specific CD8+ T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T cell response are programmed. However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-γ production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8+ T cell– and IFN-γ–dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

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