scholarly journals Prolonged Dominance of Clonally Restricted CD4+ T Cells in Macaques Infected with Simian Immunodeficiency Viruses

2000 ◽  
Vol 74 (16) ◽  
pp. 7442-7450 ◽  
Author(s):  
Zheng W. Chen ◽  
Yun Shen ◽  
Zhongchen Kou ◽  
Chris Ibegbu ◽  
Dejiang Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Temporal Association ◽  
Cell Populations ◽  
Specific Cell ◽  
Cell Repertoire ◽  
Immunodeficiency Virus ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

ABSTRACT The repertoire of functional CD4+ T lymphocytes in human immunodeficiency virus type 1-infected individuals remains poorly understood. To explore this issue, we have examined the clonality of CD4+ T cells in simian immunodeficiency virus (SIV)-infected macaques by assessing T-cell receptor complementarity-determining region 3 (CDR3) profiles and sequences. A dominance of CD4+ T cells expressing particular CDR3 sequences was identified within certain Vβ-expressing peripheral blood lymphocyte subpopulations in the infected monkeys. Studies were then done to explore whether these dominant CD4+ T cells represented expanded antigen-specific cell subpopulations or residual cells remaining in the course of virus-induced CD4+ T-cell depletion. Sequence analysis revealed that these selected CDR3-bearing CD4+ T-cell clones emerged soon after infection and dominated the CD4+ T-cell repertoire for up to 14 months. Moreover, inoculation of chronically infected macaques with autologous SIV-infected cell lines to transiently increase plasma viral loads in the monkeys resulted in the dominance of these selected CDR3-bearing CD4+ T cells. Both the temporal association of the detection of these clonal cell populations with infection and the dominance of these cell populations following superinfection with SIV suggest that these cells may be SIV specific. Finally, the inoculation of staphylococcal enterotoxin B superantigen into SIV-infected macaques uncovered a polyclonal background underlying the few dominant CDR3-bearing CD4+ T cells, demonstrating that expandable polyclonal CD4+ T-cell subpopulations persist in these animals. These results support the notions that a chronic AIDS virus infection can induce clonal expansion, in addition to depletion of CD4+ T cells, and that some of these clones may be SIV specific.

scholarly journals T-Cell Receptor Vβ Repertoire CDR3 Length Diversity Differs within CD45RA and CD45RO T-Cell Subsets in Healthy and Human Immunodeficiency Virus-Infected Children

2000 ◽  
Vol 7 (6) ◽  
pp. 953-959 ◽  
Author(s):  
Zhong Chen Kou ◽  
Joshua S. Puhr ◽  
Mabel Rojas ◽  
Wayne T. McCormack ◽  
Maureen M. Goodenow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cdr3 Length ◽  
Immunodeficiency Virus ◽  
Tcr Repertoire ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

ABSTRACT The T-cell receptor (TCR) CDR3 length heterogeneity is formed during recombination of individual Vβ gene families. We hypothesized that CDR3 length diversity could be used to assess the fundamental differences within the TCR repertoire of CD45RA and CD45RO T-cell subpopulations. By using PCR-based spectratyping, nested primers for all 24 human Vβ families were developed to amplify CDR3 lengths in immunomagnetically selected CD45RA and CD45RO subsets within both CD4+ and CD8+ T-cell populations. Umbilical cord blood mononuclear cells or peripheral blood mononuclear cells obtained from healthy newborns, infants, and children, as well as human immunodeficiency virus (HIV)-infected children, were analyzed. All T-cell subsets from newborn and healthy children demonstrated a Gaussian distribution of CDR3 lengths in separated T-cell subsets. In contrast, HIV-infected children had a high proportion of predominant CDR3 lengths within both CD45RA and CD45RO T-cell subpopulations, most commonly in CD8+ CD45RO T cells. Sharp differences in clonal dominance and size distributions were observed when cells were separated into CD45RA or CD45RO subpopulations. These differences were not apparent in unfractionated CD4+ or CD8+ T cells from HIV-infected subjects. Sequence analysis of predominant CDR3 lengths revealed oligoclonal expansion within individual Vβ families. Analysis of the CDR3 length diversity within CD45RA and CD45RO T cells provides a more accurate measure of disturbances in the TCR repertoire than analysis of unfractionated CD4 and CD8 T cells.

Probing the Impact of AMD3100/GCSF Mobilization on the Peripheral Blood T Cell Content Using a Rhesus Macaque Model: Increased Proportions of FoxP3+/CD4+ T Cells Occur After Mobilization and Leukapheresis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 350-350
Author(s):  
Leslie Kean ◽  
Sharon Sen ◽  
Mark E Metzger ◽  
Aylin Bonifacino ◽  
Karnail Singh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cell Populations ◽  
Macaque Model ◽  
Cd34 Cells ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

Abstract Abstract 350 Introduction: Leukapheresis is a widely utilized modality for collecting hematopoietic stem cells (HSCs). While collection of CD34+ cells with stem-cell activity is the primary goal of most mobilization and leukapheresis procedures, these cells only represent ∼1% of most leukapheresis products. The profile of the non-CD34+ cells is likely influenced by the choice of mobilization strategy, and has the potential to profoundly impact the post-transplant immune milieu of the transplant recipient. Two of the most critical of the CD34-negative cell populations that are collected during leukapheresis include effector and regulatory T cells. Thus, in evaluating mobilization regimens, the impact on these regimens on the mobilization of each of these T cell populations into the peripheral blood should be rigorously evaluated. Methods: We used a rhesus macaque model to determine the impact that mobilization with AMD3100 (a.k.a., Plerixafor or Mozobil®)+ G-CSF (“A+G”) had on peripheral blood CD4+ and CD8+ effector T cell populations as well as on FoxP3+/CD4+ T cells. Three rhesus macaques were mobilized with 10ug/kg SQ of G-CSF for five consecutive days prior to leukapheresis. AMD3100 was administered at 1mg/kg SQ in combination with the last dose of G-CSF two hours prior to leukapheresis. Leukapheresis procedures were performed for two hours using a modified CS3000 Plus cell separator. A peripheral blood sample was taken before cytokine therapy, just prior to leukapheresis following mobilization, one hour during leukapheresis, and at the end of the procedure. These samples were analyzed by multicolor flow cytometry using a BD LSRII flow cytometer. Results: Bulk, effector, and regulatory T cell subpopulations were analyzed flow cytometrically. The proportion of total CD3+ T cells remained stable during mobilization and apheresis: Thus, CD3+ T cells represented 77% of peripheral blood lymphocytes prior to mobilization, and 69% post-apheresis). The balance of CD4+ to CD8+ T cells was also relatively stable. Thus, for one of the three animals tested, the CD4+ and CD8+ proportions remained unchanged after apheresis. For two animals, the average CD4+ % decreased from 67% prior to mobilization to 52% post-apheresis. In these two animals, there was a reciprocal increase in the % of CD3+ T cells that were CD8+ (28% pre-G+A to 40% post-apheresis). The CD28+/CD95- naïve (Tn), CD28+/CD95+ central memory (Tcm) and CD28-/CD95+ effector memory (Tem) subpopulation balance of CD4+ and CD8+ T cells was also determined, by comparing the relative percentages of each subpopulation post-apheresis with their relative percentages prior to mobilization. Compared to their pre-G+A percentages, the post-apheresis CD4+ percentages of Tn, Tcm and Tem were 92%, 93% and 160%, respectively. Thus, the relative proportions of Tn and Tcm CD4+ cells decreased post-apheresis, while the relative proportion of CD4+ Tem increased compared to cytokine administration. For CD8+ T cell subpopulations, the post-apheresis proportions of Tn, Tcm, and Tem compared to their pre-G-CSF proportions were 99%, 70% and 130%, respectively–thus demonstrating the same direction of change as observed for CD4+ T cells. The most striking change in T cell subpopulations occurred in the CD4+/FoxP3+ compartment. The proportion of CD4+ T cells expressing FoxP3 increased by an average of 600% when post-apheresis samples were compared to pre-mobilization samples (FoxP3+ cells were 9.6% of CD4+ T cells post-apheresis versus 1.5% pre-GCSF). An average of 32% of these FoxP3+ CD4+ T cells expressed high levels of CXCR4. CXCR4 expression has been previously documented on human FoxP3+ T cells (Zou et al., Cancer Res, 2004), but this is the first observation of high level expression of CXCR4 on macaque FoxP3+ CD4 T cells, or of their ability to be efficiently mobilized with AMD3100. Discussion: These results suggest that treatment with AMD3100 and G-CSF may mobilize T cell subsets into the peripheral blood that could have beneficial effects during allo-transplantation. The combination of an increase in Tem cells, which have been observed to have decreased ability to cause GvHD (Zheng et al., Blood 2008), along with FoxP3+/CD4+ T cells, which may have regulatory functions, suggests that A+G mobilization could produce an apheresis product with a beneficial CD34-negative cell profile for allogeneic transplantation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Single-Cell TCR and Transcriptome Analysis: An Indispensable Tool for Studying T-Cell Biology and Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Pasetto ◽  
Yong-Chen Lu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cancer Immunotherapy ◽  
Transcriptome Analysis ◽  
Cell Biology ◽  
Cell Receptor ◽  
Cell Subpopulations ◽  
Indispensable Tool ◽  
T Cell Subpopulations

T cells have been known to be the driving force for immune response and cancer immunotherapy. Recent advances on single-cell sequencing techniques have empowered scientists to discover new biology at the single-cell level. Here, we review the single-cell techniques used for T-cell studies, including T-cell receptor (TCR) and transcriptome analysis. In addition, we summarize the approaches used for the identification of T-cell neoantigens, an important aspect for T-cell mediated cancer immunotherapy. More importantly, we discuss the applications of single-cell techniques for T-cell studies, including T-cell development and differentiation, as well as the role of T cells in autoimmunity, infectious disease and cancer immunotherapy. Taken together, this powerful tool not only can validate previous observation by conventional approaches, but also can pave the way for new discovery, such as previous unidentified T-cell subpopulations that potentially responsible for clinical outcomes in patients with autoimmunity or cancer.

Neopterin estimation compared with the ratio of T-cell subpopulations in persons infected with human immunodeficiency virus-1.

1988 ◽  
Vol 34 (12) ◽  
pp. 2415-2417 ◽  
Author(s):  
D Fuchs ◽  
M Banekovich ◽  
A Hausen ◽  
J Hutterer ◽  
G Reibnegger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immunodeficiency Virus ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

Abstract We measured neopterin, a biochemical indicator for the activation of cell-mediated immune reactions, in urines from 105 individuals at risk of infection with human immunodeficiency virus-1 (HIV-1), 83 of whom were seropositive for antibody to HIV-1. We compared absolute numbers of T-cell subsets (CD4+ helper/inducer T-cells, CD8+ suppressor/cytotoxic T-cells), and the ratio of CD4+ T-cells to CD8+ T-cells with the urinary neopterin concentrations. Concentrations of neopterin in urine were inversely correlated with absolute numbers of CD4+ T-cells and with CD4+/CD8+ ratios in anti-HIV-1 seropositive subjects but not in those seronegative. Various statistical comparisons of the data further demonstrated that neopterin concentrations showed larger differences between anti-HIV-1 seronegative and seropositive subjects than absolute numbers of CD4+ T-cells or CD4+/CD8+ ratios. These results seem to indicate that neopterin concentrations increase earlier in the course of HIV-1 infection, before effects on T-cell subpopulations are detectable, and may further support the suggestion that neopterin measurement could be of use for monitoring infected subjects or predicting the progression of disease.

scholarly journals Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 274
Author(s):  
Claudia Curci ◽  
Angela Picerno ◽  
Nada Chaoul ◽  
Alessandra Stasi ◽  
Giuseppe De Palma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Double Negative ◽  
Chronic Injury ◽  
Peripheral Blood Mononuclear ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.

scholarly journals Disproportion in T-cell subpopulations in immunodeficient mutant hr/hr mice.

1979 ◽  
Vol 149 (1) ◽  
pp. 228-233 ◽  
Author(s):  
A B Reske-Kunz ◽  
M P Scheid ◽  
E A Boyse
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
Salient Feature ◽  
Mutant Gene ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Mice of the HRS strain, which carry the mutant gene hr, were examined for abnormalities in representation of the three T-cell sets Ly1, Ly23, and Ly123 in the spleen. The salient feature of hr/hr mice, which are immunologically deficient, in comparison with +/hr segregants, was a gross disproportion in numbers of cells belonging to the Ly1 and Ly123 sets, at the age of 3--3.5 mo. At this age, Ly123 cells of hr/hr spleen outnumbered Ly1 cells by 2:1, whereas in +/hr spleens Ly123 cells were outnumbered by approximately 1:2. Cells from pooled lymph nodes of hr/hr mice did not show a correspondingly gross disporprotion of Ly1 and Ly123 cells. Total counts of splenic T cells, and of B cells, were not significantly different in hr/hr and +/hr mice.

scholarly journals Characterization of Changes in the T-Cell Receptor Repertoire in Patients with Acute Myeloid Leukemia with Durable Remission Following Allogeneic Stem Cell Transplant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5186-5186
Author(s):  
Ronald M. Paranal ◽  
Hagop M. Kantarjian ◽  
Alexandre Reuben ◽  
Celine Kerros ◽  
Priya Koppikar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Donor T Cells ◽  
Durable Remission

Introduction: Allogeneic hematopoietic stem-cell transplantation (HSCT) is curative for many patients with advanced hematologic cancers, including adverse-risk acute myeloid leukemia (AML). This is principally through the induction of a graft-versus-leukemia (GVL) immune effect, mediated by donor T-cells. The incredible diversity and specificity of T-cells is due to rearrangement between V, D, and J regions and the random insertion/deletion of nucleotides, taking place in the hypervariable complementarity determining region 3 (CD3) of the T-cell receptor (TCR). Massively parallel sequencing of CDR3 allows for a detailed understanding of the T-cell repertoire, an area relatively unexplored in AML. Therefore, we sought out to characterize the T-cell repertoire in AML before and after HSCT, specifically for those with a durable remission. Methods: We identified 45 bone marrow biopsy samples, paired pre- and post-HSCT, from 14 patients with AML in remission for > 2 years as of last follow-up. We next performed immunosequencing of the TCRβ repertoire (Adaptive Biotechnologies). DNA was amplified in a bias-controlled multiplex PCR, resulting in amplification of rearranged VDJ segments, followed by high-throughput sequencing. Resultant sequences were collapsed and filtered in order to identify and quantitate the absolute abundance of each unique TCRβ CDR3 region. We next employed various metrics to characterize changes in the TCR repertoire: (1) clonality (range: 0-1; values closer to 1 indicate a more oligoclonal repertoire), it accounts for both the number of unique clonotypes and the extent to which a few clonotypes dominate the repertoire; (2) richness with a higher number indicating a more diverse repertoire with more unique rearrangements); (3) overlap (range: 0-1; with 1 being an identical T-cell repertoire). All calculations were done using the ImmunoSeq Analyzer software. Results: The median age of patients included in this cohort was 58 years (range: 31-69). Six patient (43%) had a matched related donor, and 8 (57%) had a matched unrelated donor. Baseline characteristics are summarized in Figure 1A. Six samples were excluded from further analysis due to quality. TCR richness did not differ comparing pre- and post-HSCT, with a median number pre-HSCT of 3566 unique sequences (range: 1282-22509) vs 3720 (range: 1540-12879) post-HSCT (P = 0.7). In order to assess whether there was expansion of certain T-cell clones following HSCT, we employed several metrics and all were indicative of an increase in clonality (Figure 2B). Productive clonality, a measure of reactivity, was significantly higher in post-transplant samples (0.09 vs 0.02, P = 0.003). This is a measure that would predict expansion of sequences likely to produce functional TCRs. The Maximum Productive Frequency Index was higher post-HSCT indicating that the increase in clonality was driven by the top clone (most prevalent per sample). Similarly for the Simpson's Dominance index, another marker of clonality which was higher post-HSCT (0.01 vs 0.0009, P = 0.04). In order to determine whether this clonal expansion was driven by TCR clones shared among patients, we compared the degree of overlap in unique sequences among pre and post-HSCT samples. We found there was very little overlap between samples in the pre and the post-transplant setting and no change in the Morisita and Jaccard Overlap Indices. Conclusions: In conclusion, we show in this analysis an increase in clonality of T-cells following HSCT in patients with AML. This is likely related to the GVL effect after recognition of leukemia antigens by donor T cells and subsequent expansion of these T-cells. These expanded T-cell clonotypes were unlikely to be shared by patients in this cohort, likely reflecting the variety of antigens leading to the GVL effect. This could have direct implications on TCR-mediated immune-therapies given the likely need for a personalized, patient-specific design for these therapies. Figure 1 Disclosures Kantarjian: BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Cortes:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties.

scholarly journals Circulating CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Individuals Have Impaired Function and Downmodulate CD3ζ, the Signaling Chain of the T-Cell Receptor Complex

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 585-594 ◽  
Author(s):  
Linda A. Trimble ◽  
Judy Lieberman
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Complex ◽  
Cd8 T Lymphocytes ◽  
Immunodeficiency Virus ◽  
Specific Cytotoxicity

Although human immunodeficiency virus (HIV)-infected subjects without acquired immunodeficiency syndrome have a high frequency of HIV-specific CD8 T lymphocytes, freshly isolated lymphocytes frequently lack detectable HIV-specific cytotoxicity. However, this effector function becomes readily apparent after overnight culture. To investigate reasons for T-cell dysfunction, we analyzed T-cell expression of the cytolytic protease granzyme A and of CD3ζ, the signaling component of the T-cell receptor complex. An increased proportion of CD4 and CD8 T cells from HIV-infected donors contain granzyme A, consistent with the known increased frequency of activated T cells. In 28 HIV-infected donors with mild to advanced immunodeficiency, a substantial fraction of circulating T cells downmodulated CD3ζ (fraction of T cells expressing CD3ζ, 0.74 ± 0.16 v 1.01 ± 0.07 in healthy donors; P < .0000005). CD3ζ expression is downregulated more severely in CD8 than CD4 T cells, decreases early in infection, and correlates with declining CD4 counts and disease stage. CD3ζ expression increases over 6 to 16 hours of culture in an interleukin-2–dependent manner, coincident with restoration of viral-specific cytotoxicity. Impaired T-cell receptor signaling may help explain why HIV-specific cytotoxic T lymphocytes fail to control HIV replication.

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