scholarly journals Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

2021 ◽  
Vol 2 ◽  
Author(s):  
Josien Lanfermeijer ◽  
Peter C. de Greef ◽  
Marion Hendriks ◽  
Martijn Vos ◽  
Josine van Beek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
T Cell Repertoire ◽  
Cmv Infection ◽  
Constant Input ◽  
Cell Repertoire ◽  
Cell Pool ◽  
Age Related ◽  
Tcr Diversity

CD8+ T cells play an important role in protection against viral infections. With age, changes in the T-cell pool occur, leading to diminished responses against both new and recurring infections in older adults. This is thought to be due to a decrease in both T-cell numbers and T-cell receptor (TCR) diversity. Latent infection with cytomegalovirus (CMV) is assumed to contribute to this age-associated decline of the immune system. The observation that the level of TCR diversity in the total memory T-cell pool stays relatively stable during aging is remarkable in light of the constant input of new antigen-specific memory T cells. What happens with the diversity of the individual antigen-specific T-cell repertoires in the memory pool remains largely unknown. Here we studied the effect of aging on the phenotype and repertoire diversity of CMV-specific and Epstein-Barr virus (EBV)-specific CD8+ T cells, as well as the separate effects of aging and CMV-infection on the EBV-specific T-cell repertoire. Antigen-specific T cells against both persistent viruses showed an age-related increase in the expression of markers associated with a more differentiated phenotype, including KLRG-1, an increase in the fraction of terminally differentiated T cells, and a decrease in the diversity of the T-cell repertoire. Not only age, but also CMV infection was associated with a decreased diversity of the EBV-specific T-cell repertoire. This suggests that both CMV infection and age can impact the T-cell repertoire against other antigens.

scholarly journals Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8+ T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons

2005 ◽  
Vol 79 (6) ◽  
pp. 3675-3683 ◽  
Author(s):  
Giovanni Almanzar ◽  
Susanne Schwaiger ◽  
Brigitte Jenewein ◽  
Michael Keller ◽  
Dietmar Herndler-Brandstetter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
Growth Potential ◽  
Elderly Persons ◽  
T Cell Repertoire ◽  
Cmv Infection ◽  
Cell Repertoire ◽  
Memory T Cell ◽  
Cell Pool

ABSTRACT In spite of the present belief that latent cytomegalovirus (CMV) infection drives CD8+ T-cell differentiation and induces premature immune senescence, no systematic studies have so far been performed to compare phenotypical and functional changes in the CD8+ T-cell repertoire in CMV-infected and noninfected persons of different age groups. In the present study, number, cytokine production, and growth potential of naïve (CD45RA+ CD28+), memory (CD45RA− CD28+), and effector (CD45RA+ CD28− or CD45RA− CD28−) CD8+ T cells were analyzed in young, middle-aged, and elderly clinically healthy persons with a positive or negative CMV antibody serology. Numbers and functional properties of CMVpp65495-503-specific CD8+ T cells were also studied. We demonstrate that aging as well as CMV infection lead to a decrease in the size of the naïve CD8+ T-cell pool but to an increase in the number of CD8+ effector T cells, which produce gamma interferon but lack substantial growth potential. The size of the CD8+ memory T-cell population, which grows well and produces interleukin-2 (IL-2) and IL-4, also increases with aging, but this increase is missing in CMV carriers. Life-long latent CMV infection seems thus to diminish the size of the naïve and the early memory T-cell pool and to drive a Th1 polarization within the immune system. This can lead to a reduced diversity of CD8 responses and to chronic inflammatory processes which may be the basis of severe health problems in elderly persons.

scholarly journals Fidelity of the repertoire in T cell reconstituted athymic nude rats. Preservation of a deficit in alloresponsiveness over one year.

1989 ◽  
Vol 170 (3) ◽  
pp. 691-702 ◽  
Author(s):  
M T Drayson ◽  
S M Sparshott ◽  
E B Bell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Thoracic Duct ◽  
Rapid Expansion ◽  
Third Party ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Self Renewal ◽  
Cell Pool ◽  
Nude Rats

A single intravenous injection of a relatively small number of T cells contained in the population of rat thoracic duct lymphocytes (TDL) is sufficient to restore to normal the peripheral T cell pool of athymic PVG.rnu/rnu nude rats. The donor T cells expand greater than 10-15-fold, self-renew, and restore immunocompetency to nude recipients permanently (greater than 2 yr). We asked whether the T cell repertoire was affected by the expansion and self-renewal process. Nude recipients were injected with syngeneic PVG TDL that had been allospecifically depleted (negatively selected) by consecutive passage from blood to thoracic duct lymph through two irradiated (DAxPVG)F1 intermediate rats. Negatively selected TDL were tested before transfer by the P----F1 popliteal LN GVH assay and showed a greater than 90% depletion of specific reactivity to DA alloantigens. Surviving cells or their progeny were recovered from LN or TDL of nude recipients 8 and 12 mo after transfer. The deficit in GVH reactivity to the DA haplotype persisted, but normal GVH activity was demonstrated against a third party (AOxPVG)F1 alloantigen. The "hole" in the repertoire could not be attributed to tolerance induced by the co-transfer of contaminating irradiated F1 TDL. PVG TDL passaged consecutively through (AOxPVG)F1 and (DAxPVG)F1 intermediates and devoid of (AOxPVG)F1 cells remained specifically depleted to both AO and DA haplotypes when recovered from nude recipients 4 and 13 mo later, but displayed GVH activity to a third-party (BNxPVG)F1 alloantigen. Thus the exact specificity of the T cell repertoire of the original inoculum was faithfully maintained in nude recipients throughout the initial phase of rapid expansion and the continued self-renewal of the mature peripheral T cell pool.

Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3020-3020
Author(s):  
Edward Cha ◽  
Yafei Hou ◽  
Mark Klinger ◽  
Craig Cummings ◽  
Malek Faham ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Multiple Time ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antibody Treatment ◽  
Tcr Repertoire ◽  
Tcr Diversity ◽  
Morisita Index

3020 Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencing-based method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.

Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4283-4292 ◽  
Author(s):  
Katherine K. Wynn ◽  
Zara Fulton ◽  
Leanne Cooper ◽  
Sharon L. Silins ◽  
Stephanie Gras ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
Structural Features ◽  
T Cell Response ◽  
Helical Conformation ◽  
T Cell Repertoire ◽  
Cell Repertoire

AbstractCD8+ T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However, the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)–specific CD8+ T cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public T-cell repertoire or a private, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)–peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while a diverse TCR profile was observed in response to the epitope that formed a flatter, more “featureless” landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared with the T cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its phenotype.

scholarly journals Age-related CD8 T Cell Clonal Expansions Constrict CD8 T Cell Repertoire and Have the Potential to Impair Immune Defense

2004 ◽  
Vol 200 (10) ◽  
pp. 1347-1358 ◽  
Author(s):  
Ilhem Messaoudi ◽  
Joël LeMaoult ◽  
Jose A. Guevara-Patino ◽  
Beatrix M. Metzner ◽  
Janko Nikolich-Žugich
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Immune Defense ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Age Related ◽  
Cell Diversity ◽  
Hsv 1

Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8+ T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results in reduced CD8+, but not CD4+, T cell diversity, and in functional inability to mobilize parts of the CD8+ T cell repertoire affected by TCE. In the model of herpes simplex virus (HSV)-1 infection of B6 mice, >90% of the responding CD8+ T cells use Vβ10 or Vβ8 and are directed against a single glycoprotein B (gB498-505) epitope, gB-8p. We found that old animals bearing CD8+ TCE within Vβ10 or Vβ8 families failed to mount an effective immune response against HSV-1, as judged by reduced numbers of peptide-major histocompatibility complex tetramer+ CD8 T cells and an absence of antiviral lytic function. Furthermore, Vβ8 TCE experimentally introduced into young mice resulted in lower resistance to viral challenge, whereas Vβ5+ TCE induced in a similar fashion did not impact viral resistance. These results demonstrate that age-related TCE functionally impair the efficacy of antiviral CD8+ T cell immunity in an antigen-specific manner, strongly suggesting that TCE are not the mere manifestation of, but are also a contributing factor to, the immunodeficiency of senescence.

scholarly journals Polyclonal expansion of TCR Vbeta 21.3+ CD4+ and CD8+ T cells is a hallmark of Multisystem Inflammatory Syndrome in Children

2021 ◽  
Vol 6 (59) ◽  
pp. eabh1516
Author(s):  
Marion Moreews ◽  
Kenz Le Gouge ◽  
Samira Khaldi-Plassart ◽  
Rémi Pescarmona ◽  
Anne-Laure Mathieu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Healthy Children ◽  
Antigenic Peptides ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Hla Dr ◽  
T Cell Expansion ◽  
Inflammatory Syndrome

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

scholarly journals 762 A combination of functional biomarkers improves identification of the tumor-specific reactive T cell repertoire

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A810-A810
Author(s):  
Arianna Draghi ◽  
Katja Harbst ◽  
Inge Svane ◽  
Marco Donia
Keyword(s):  
T Cells ◽  
T Cell ◽  
De Novo ◽  
Autologous Tumor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Simple Method ◽  
Functional Biomarkers

BackgroundDetecting the entire repertoire of tumor-specific reactive T cells is essential for investigating the broad range of T cell functions in the tumor-microenvironment. At present, assays identifying tumor-specific functional activation measure either upregulation of specific surface molecules, de novo production of the most common antitumor cytokines or mobilization of cytotoxic granules.MethodsIn this study, we combined transcriptomic analyses of tumor-specific reactive tumorinfiltrating lymphocytes (TILs), TIL-autologous tumor cell co-cultures and commonly used established detection protocols to develop an intracellular flow cytometry staining method encompassing simultaneous detection of intracellular CD137, de novo production of TNF and IFNy and extracellular mobilization of CD107a.ResultsThis approach enabled the identification of a larger fraction of tumor-specific reactive T cells in vitro compared to standard methods, revealing the existence of multiple distinct functional clusters of tumor-specific reactive TILs. Publicly available datasets of fresh tumor single-cell RNA-sequencing from four cancer types were investigated to confirm that these functional biomarkers identified distinct functional clusters forming the entire repertoire of tumor-specific reactive T cells in situ.ConclusionsIn conclusion, we describe a simple method using a combination of functional biomarkers that improves identification of the tumor-specific reactive T cell repertoire in vitro and in situ.

scholarly journals Characterization of human cytomegalovirus peptide–specific CD8+ T-cell repertoire diversity following in vitro restimulation by antigen-pulsed dendritic cells

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 213-223 ◽  
Author(s):  
Karl Peggs ◽  
Stephanie Verfuerth ◽  
Arnold Pizzey ◽  
Jenni Ainsworth ◽  
Paul Moss ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Repertoire Diversity ◽  
Clonal Composition

Under conditions of impaired T-cell immunity, human cytomegalovirus (HCMV) can reactivate from lifelong latency, resulting in potentially fatal disease. A crucial role for CD8+ T cells has been demonstrated in control of viral replication, and high levels of HCMV-specific cytotoxic T-lymphocytes are seen in immunocompetent HCMV-seropositive individuals despite very low viral loads. Elucidation of the minimum portion of the anti-HCMV T-cell repertoire that is required to suppress viral replication requires further study of clonal composition. The ability of dendritic cells to take up and process exogenous viral antigen by constitutive macropinocytosis was used to study HCMV-specific T-cell memory in the absence of viral replication. The specificity and clonal composition of the CD8+ T-cell responses were evaluated using HLA tetrameric complexes and T-cell receptor β chain (TCRBV) spectratypic analyses. There was a skewed reactivity toward the matrix protein pp65, with up to 40-fold expansion of CD8+ T cells directed toward a single peptide-MHC combination. Individual expansions detected on TCRBV spectratype analysis were HCMV-specific and composed of single or highly restricted numbers of clones. There was preferential TCRBV gene usage (BV6.1/6.2, BV8, and BV13 in HLA-A*0201+ individuals) but lack of conservation of CDR3 length and junctional motifs between donors. While there was a spectrum of TCR repertoire diversity directed toward individual MHC-peptide combinations between donors, a relatively small number of clones appeared to predominate the response in each case. These data provide further insight into the range of anti-HCMV responses and will aid the design and monitoring of adoptive immunotherapy protocols.

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