scholarly journals Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection

2015 ◽  
Vol 89 (8) ◽  
pp. 4517-4526 ◽  
Author(s):  
William S. DeWitt ◽  
Ryan O. Emerson ◽  
Paul Lindau ◽  
Marissa Vignali ◽  
Thomas M. Snyder ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Viral Infection ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
T Cell Clones ◽  
Cell Clones ◽  
Acute Viral Infection

ABSTRACTA detailed characterization of the dynamics and breadth of the immune response to an acute viral infection, as well as the determinants of recruitment to immunological memory, can greatly contribute to our basic understanding of the mechanics of the human immune system and can ultimately guide the design of effective vaccines. In addition to neutralizing antibodies, T cells have been shown to be critical for the effective resolution of acute viral infections. We report the first in-depth analysis of the dynamics of the CD8+T cell repertoire at the level of individual T cell clonal lineages upon vaccination of human volunteers with a single dose of YF-17D. This live attenuated yellow fever virus vaccine yields sterile, long-term immunity and has been previously used as a model to understand the immune response to a controlled acute viral infection. We identified and enumerated unique CD8+T cell clones specifically induced by this vaccine through a combined experimental and statistical approach that included high-throughput sequencing of the CDR3 variable region of the T cell receptor β-chain and an algorithm that detected significantly expanded T cell clones. This allowed us to establish that (i) on average, ∼2,000 CD8+T cell clones were induced by YF-17D, (ii) 5 to 6% of the responding clones were recruited to long-term memory 3 months postvaccination, (iii) the most highly expanded effector clones were preferentially recruited to the memory compartment, and (iv) a fraction of the YF-17D-induced clones could be identified from peripheral blood lymphocytes solely by measuring clonal expansion.IMPORTANCEThe exhaustive investigation of pathogen-induced effector T cells is essential to accurately quantify the dynamics of the human immune response. The yellow fever vaccine (YFV) has been broadly used as a model to understand how a controlled, self-resolving acute viral infection induces an effective and long-term protective immune response. Here, we extend this previous work by reporting the identity of activated effector T cell clones that expand in response to the YFV 2 weeks postvaccination (as defined by their unique T cell receptor gene sequence) and by tracking clones that enter the memory compartment 3 months postvaccination. This is the first study to use high-throughput sequencing of immune cells to characterize the breadth of the antiviral effector cell response and to determine the contribution of unique virus-induced clones to the long-lived memory T cell repertoire. Thus, this study establishes a benchmark against which future vaccines can be compared to predict their efficacy.

scholarly journals Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra46-332ra46 ◽  
Author(s):  
Qian Qi ◽  
Mary M. Cavanagh ◽  
Sabine Le Saux ◽  
Hong NamKoong ◽  
Chulwoo Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Chronic Infection ◽  
Cell Receptor ◽  
Control Mechanisms ◽  
Cell Repertoire ◽  
T Cell Clones ◽  
Varicella Zoster ◽  
Cell Clones

Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen–reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

scholarly journals Localization of T cell clonotypes using spatial transcriptomics

2021 ◽  
Author(s):  
William H. Hudson ◽  
Lisa J. Sudmeier
Keyword(s):  
T Cell ◽  
Spatial Organization ◽  
Spatial Information ◽  
Human Tumor ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Archived Samples

Spatial transcriptomics is an emerging technology that measures gene expression while preserving spatial information. Here, we present a method to determine localization of specific T cell clones by obtaining T cell receptor (TCR) sequences from spatial transcriptomics assays. Our method uses an existing commercial spatial transcriptomics platform and open-source software for analysis, allowing simple and inexpensive integration with archived samples and existing laboratory workflows. Using human brain metastasis samples, we show that TCR sequences are readily obtained from human tumor tissue and that these sequences are recapitulated by single-cell sequencing methods. This technique will permit detailed studies of the spatial organization of the human T cell repertoire, such as the identification of tumor- infiltrating and tumor-excluded T cell clones.

Long-Term Culture and T Cell Receptor Analysis of T Cell Clones Isolated from a Patient with Adenosine Deaminase Deficiency and Type I Diabetes

1994 ◽  
Vol 73 (3) ◽  
pp. 362-366 ◽  
Author(s):  
Piergiuseppe De Berardinis ◽  
Maria Neve Ombra ◽  
Catello Buono ◽  
Roberto Toraldo ◽  
Francesco Vetrano ◽  
...  
Keyword(s):  
T Cell ◽  
Adenosine Deaminase ◽  
T Cell Receptor ◽  
Type I Diabetes ◽  
Cell Receptor ◽  
Type I ◽  
Adenosine Deaminase Deficiency ◽  
T Cell Clones ◽  
Cell Clones

T Cell Repertoire Diversity After Umbilical Cord Transplant Predicts Mortality From Infection

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4202-4202 ◽  
Author(s):  
Colleen Delaney ◽  
Ryan O Emerson ◽  
Filippo Milano ◽  
Anna Sherwood ◽  
Adrienne Papermaster ◽  
...  
Keyword(s):  
T Cell ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
T Cell Clones ◽  
Cell Clones ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Equity Ownership

Abstract Abstract 4202 Background In a transplant study run at Fred Hutchinson Cancer Research Center, 34 patients with high risk hematological malignancies underwent a myeloablative procedure and were subsequently transplanted with double umbilical cord blood units. Peripheral blood samples were collected from each patient before myeloablation, and at 28, 56, 100, 180, and 360 days post-transplant. Methods At each time point, we used the immunoSEQ platform to perform high-throughput sequencing of rearranged T Cell Receptor (TCR) loci. Using immunoSEQ data, we were able to track the presence and frequency of individual TCR clones in each patient across time-points, as well as measuring the diversity of the TCR repertoire as a whole. We correlated our measure of TCR repertoire diversity with clinical outcomes in this cohort. Results The study produced two primary results. First, using the ability to track clones, the reconstituting TCR repertoire is shown to oscillate wildly with nearly complete turnover of the T cell repertoire occurring at least monthly after CB transplant. The largest T cell clones present in each blood draw drop below detection within weeks, contrasting with control data in which the top clones in healthy patients are not only observed in multiple subsequent time-points, but remain at high frequency. The second result is a test of the hypothesis that diversity of the T cell repertoire is a measure of immunocompetence, as a clinical application of high-throughput sequencing. Of the 34 patients, six died between Day 100 and Day 360 of non-relapse causes. At both Day 56 and Day 100, the diversity of the T cell repertoires of those six patients were far lower than the T cell repertoire diversity values of the remaining patients (P-value = 0.015). Conclusions We have demonstrated that the reconstitution of clinical immunity in cord blood transplantation patients is characterized by a highly unstable T cell compartment with very rapid turnover of T cell clones. Despite the transience of individual T cell clones, however, by two months after transplant T cell repertoire diversity as measured by high-throughput TCR sequencing accurately predicts risk of non-relapse mortality. Disclosures: Emerson: Adaptive Biotechnologies: Employment, Equity Ownership. Sherwood:Adaptive Biotechnologies: Employment, Equity Ownership. Carlson:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals Self-sparing of long-term in vitro-cloned or uncloned cytotoxic T lymphocytes.

1986 ◽  
Vol 164 (3) ◽  
pp. 962-967 ◽  
Author(s):  
M F Luciani ◽  
J F Brunet ◽  
M Suzan ◽  
F Denizot ◽  
P Golstein
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cytotoxic T Cell ◽  
Cell Populations ◽  
Con A ◽  
T Cell Clones ◽  
Cell Clones

At least some long-term in vitro-cultured cytotoxic T cell clones and uncloned cell populations are able, in the presence of Con A, to lyse other cells, to be lysed by other cells, but not to lyse themselves. This as-yet-unexplained result may have implications as to the mechanism of T cell-mediated cytotoxicity.

scholarly journals Generation of Cytomegalovirus-Specific Human T-Lymphocyte Clones by Using Autologous B-Lymphoblastoid Cells with Stable Expression of pp65 or IE1 Proteins: a Tool To Study the Fine Specificity of the Antiviral Response

2000 ◽  
Vol 74 (9) ◽  
pp. 3948-3952 ◽  
Author(s):  
Christelle Retière ◽  
Virginie Prod'homme ◽  
Berthe-Marie Imbert-Marcille ◽  
Marc Bonneville ◽  
Henri Vié ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Relevant Information ◽  
In Vitro Models ◽  
T Cell Clones ◽  
Fine Specificity ◽  
Early Protein ◽  
Cell Clones ◽  
Human T Lymphocyte

ABSTRACT Cytotoxic T lymphocytes (CTLs) play a central role in the control of persistent human cytomegalovirus (HCMV) infection in healthy virus carriers. Previous analyses of the specificity of HCMV-reactive CD8+ CTLs drawn from in vitro models in which antigen-presenting cells were autologous fibroblasts infected with laboratory HCMV strains have shown focusing of CTL responses against the major tegument protein, pp65. By contrast, the 72-kDa major immediate-early protein (IE1) was identified as a minor target for this response. Here we have studied the fine specificity and T-cell-receptor features of T-cell clones generated against autologous B lymphoblastoid cell lines stably transfected with HCMV cDNA coding for either pp65 or a natural variant of IE1. This strategy allowed efficient generation of T-cell clones against IE1 and pp65 and led to the identification of several new IE1 and pp65 epitopes, including some located in polymorphic regions of IE1. Such an approach may provide relevant information about the characteristics of the CTL response to IE1 and the effect of viral polymorphism on the immune response against HCMV.

Macrophage-derived CXCL9 and CXCL11, T-cell skin homing and disease control in mogamulizumab-treated CTCL patients

Blood ◽  
2021 ◽  
Author(s):  
Adèle de Masson ◽  
Delphine Darbord ◽  
Gabor Dobos ◽  
Marie Boisson ◽  
Marie Roelens ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Control ◽  
High Throughput Sequencing ◽  
Sequencing Analysis ◽  
Cell Clones ◽  
Skin Homing ◽  
T Cell Homing ◽  
T Cell Immune Responses

Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T-cells. Long-term remissions are rare in CTCL, and the pathophysiology of long-lasting disease control is unknown. Mogamulizumab is a defucosylated anti-human CCR4 antibody that depletes CCR4-expressing CTCL tumor cells and peripheral blood memory regulatory T cells. Prolonged remissions and immune side effects have been observed in mogamulizumab-treated CTCL patients. We report that mogamulizumab induced skin rashes in 32% of 44 CTCL patients. These rashes were associated with long-term CTCL remission, even in the absence of specific CTCL treatment. CTCL patients with mogamulizumab-induced rash had significantly higher overall survival (hazard ratio, 0.16 (0.04-0.73, p=0.01)). Histopathology and immunohistochemistry of the rashes revealed granulomatous and lichenoid patterns with CD163 macrophagic and CD8 T-cell infiltrates. Depletion of skin CTCL cells was confirmed by high-throughput sequencing analysis of TCRβ genes and in blood by flow cytometry. New reactive T-cell clones were recruited in skin. Gene expression analysis showed overexpression of CXCL9 and CXCL11, two chemokines involved in CXCR3-expressing T-cell homing to skin. Single-cell RNA sequencing analysis in skin of CTCL patients confirmed that CXCL9 and CXCL11 were primarily macrophage-derived and that skin T-cells expressed CXCR3. Finally, patients with rashes had a significantly higher proportion of exhausted reactive blood T-cells expressing TIGIT and PD1 at baseline compared to patients without rash, which decreased under mogamulizumab treatment, consistent with an activation of the antitumor immunity. Together, these data suggest that mogamulizumab may induce long-term immune control in CTCL patients by activation of the macrophagic and T-cell immune responses.

The expansion and selection of T cell receptor αβ intestinal intraepithelial T cell clones

1996 ◽  
Vol 26 (4) ◽  
pp. 914-921 ◽  
Author(s):  
Armelle Regnault ◽  
Jean-Pierre Levraud ◽  
Annick Lim ◽  
Adrien Six ◽  
Christiane Moreau ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Clones ◽  
Cell Clones ◽  
Selection Of

scholarly journals Self-reactive human CD4 T cell clones form unusual immunological synapses

2012 ◽  
Vol 209 (2) ◽  
pp. 335-352 ◽  
Author(s):  
David A. Schubert ◽  
Susana Gordo ◽  
Joseph J. Sabatino ◽  
Santosh Vardhana ◽  
Etienne Gagnon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
T Cell Clones ◽  
Cell Clones ◽  
Immunological Synapses ◽  
High Degree ◽  
Self Antigen

Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.

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