scholarly journals Defining the dynamics of naive CD4 and CD8 T cells across the mouse lifespan

2022 ◽  
Author(s):  
Sanket Rane ◽  
Thea Hogan ◽  
Edward Lee ◽  
Benedict Seddon ◽  
Andrew Yates
Keyword(s):  
T Cells ◽  
Population Dynamics ◽  
T Cell ◽  
Cd8 T Cells ◽  
Feedback Regulation ◽  
Cd8 T Cell ◽  
Environment Impact ◽  
Cell Dynamics ◽  
Naive T Cells ◽  
Naïve T Cells

Naive CD4 and CD8 T cells are part of the foundation of adaptive immune responses, but multiple aspects of their behaviour remain elusive. Newly generated T cells continue to develop after they leave the thymus and their dynamics and 'rules of entry' into the mature naive population are challenging to define. The extents to which naive T cells' capacities to survive or self-renew change as they age are also unclear. Further, much of what we know about their behaviour derives from studies in adults, both mouse and human. We know much less about naive T cell dynamics early in life, during which the thymus is highly active and peripheral T cell populations are rapidly established. For example, it has been suggested that neonatal mice are lymphopenic; if so, does this environment impact the behaviour of the earliest thymic emigrants, for example through altered rates of division and loss? In this study we integrate data from multiple experimental systems to construct models of naive CD4 and CD8 T cell population dynamics across the entire mouse lifespan. We infer that both subsets progressively increase their capacity to persist through survival mechanisms rather than through self-renewal, and find that this very simple model of adaptation describes the population dynamics of naive CD4 T cells from birth into old age. In addition, we find that newly generated naive CD8 T cells are lost at an elevated rate for the first 3-4 weeks of life, which may derive from transiently increased recruitment into conventional and virtual memory populations. We find no evidence for elevated rates of division of naive CD4 or CD8 T cells early in life and indeed estimate that these cells divide extremely rarely. Markers of proliferation within peripheral naive T cells are instead inherited from division during thymic development. We also find no evidence for feedback regulation of rates of division or loss of naive T cells at any age in healthy mice, challenging the dogma that their numbers are homeostatically regulated. Our analyses show how confronting an array of mechanistic mathematical models with diverse datasets can move us closer to a complete, and remarkably simple, picture of naive CD4 and CD8 T cell dynamics in mice.

scholarly journals Cortisol and epinephrine control opposing circadian rhythms in T cell subsets

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5134-5143 ◽  
Author(s):  
Stoyan Dimitrov ◽  
Christian Benedict ◽  
Dennis Heutling ◽  
Jürgen Westermann ◽  
Jan Born ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Circadian Rhythms ◽  
Cd8 T Cells ◽  
Low Dose ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Counts

Abstract Pronounced circadian rhythms in numbers of circulating T cells reflect a systemic control of adaptive immunity whose mechanisms are obscure. Here, we show that circadian variations in T cell subpopulations in human blood are differentially regulated via release of cortisol and catecholamines. Within the CD4+ and CD8+ T cell subsets, naive cells show pronounced circadian rhythms with a daytime nadir, whereas (terminally differentiated) effector CD8+ T cell counts peak during daytime. Naive T cells were negatively correlated with cortisol rhythms, decreased after low-dose cortisol infusion, and showed highest expression of CXCR4, which was up-regulated by cortisol. Effector CD8+ T cells were positively correlated with epinephrine rhythms, increased after low-dose epinephrine infusion, and showed highest expression of β-adrenergic and fractalkine receptors (CX3CR1). Daytime increases in cortisol via CXCR4 probably act to redistribute naive T cells to bone marrow, whereas daytime increases in catecholamines via β-adrenoceptors and, possibly, a suppression of fractalkine signaling promote mobilization of effector CD8+ T cells from the marginal pool. Thus, activation of the major stress hormones during daytime favor immediate effector defense but diminish capabilities for initiating adaptive immune responses.

scholarly journals Donor Lymphocyte Infusions Correct Deficiency of Naive T Cells and Improve T-Cell Competence after Allogeneic Haematopoietic Stem Cell Transplantation with Lymphocyte Depletion

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2233-2233
Author(s):  
Monera Al Rukhayes ◽  
Victoria T Potter ◽  
Pilar Perez-Abellan ◽  
Jesus Feliu ◽  
Lajos Floro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Haematopoietic Stem Cell ◽  
Naive T Cells ◽  
Lymphocyte Depletion ◽  
Naïve T Cells ◽  
Repertoire Diversity

Abstract Lymphocyte-depletion effectively reduces risk of graft versus host disease (GvHD) after allogeneic haematopoietic stem cell transplantation (allo-HSCT), but risk of infections and malignant disease relapse remains high. We have previously reported that pre-emptive donor lymphocyte infusions (pDLI) given to patients after allo-HSCT for myeloid malignancies to reverse falling donor T-cell chimerism improve overall and relapse-free survival. GvHD rates after pDLI were not high and grade rarely severe. To investigate the basis for better outcome after pDLI, we have assessed recovery of lymphocyte subsets, T-cell receptor (TCR) diversity and T-cell functional competence after allo-HSCT with fludarabine and busulphan in cohorts of 59 patients (median age 59) given alemtuzumab for lymphocyte-depletion and 34 patients (median age 58) given anti-thymocyte globulin (ATG). Lymphocytes were significantly less depleted with ATG compared to alemtuzumab (Day 30: Median 3.9 x 108/liter versus 2.3x108/liter, P=0.03) but numbers for both ATG and alemtuzumab remained significantly below the normal range (median 2.34x109/liter for 11 aged-matched healthy volunteers) for at least one year (Day 360 P<0.005: Median 8.35 x 108/liter after ATG; median 1.04 x 109/liter after alemtuzumab). Lymphocyte subset composition was similar after ATG or alemtuzumab, and abnormal. Notable, the T-cell population comprised only memory and effector T cells early after HSCT. These cells expressed significantly higher levels of Ki67 than T cells from healthy volunteers (Day 30 P<0.005: Median CD4 T cells 41.3% Ki67+ after ATG, 66% after alemtuzumab compared to 2.51% for healthy volunteers; median CD8 T cells 18.5% Ki67+ after ATG, 50.8% after alemtuzumab compared to 2.58% for healthy volunteers). This marker is indicative of homeostatic proliferation likely driven by increased levels of IL7 and IL15 detected in the serum of patients early after HSCT compared to healthy volunteers (Day 30 P=0.066 and P<0.005 respectively). Higher frequency of T cells expressing the proliferation marker in patients treated with alemtuzumab was associated with high frequencies of T cells expressing the PD1 marker, indicative of exhaustion (Day 30 P<0.005: Median CD4 T cells 84.0% PD1+ after alemtuzumab compared to 6.35% for healthy volunteers; median CD8 T cells 49.1% PD1+ after alemtuzumab compared to 12.3% for healthy volunteers). Expression of PD1 by T cells was near normal in patients treated with ATG. Naïve T cells were typically absent for at least six months after HSCT following lymphocyte depletion with ATG or alemtuzumab, and any subsequent recovery was poor. In contrast, the naïve T-cell population increased rapidly in patients after pDLI (n=18). Six of these patients received pDLI early after HSCT (at 3-5 months) and naïve T-cell recovery was significantly enhanced at six months compared to patients that did not receive pDLI (Day 180 P<0.005: Median 19.25% naïve CD4 T cells compared to 1.36%; median 23.5% naïve CD8 T cells compared to 3.48%). Naïve T cells are the main source of repertoire diversity and responsible for responses to antigens not previously encountered. Analysis of the TCR β chain repertoire of five patients by deep sequencing revealed that pDLI boosts repertoire diversity. For example, unique TCR β chain sequences increased 31-fold in 150 days after pDLI compared to a 2-fold increase during a similar period for another patient that did not receive DLI. Furthermore, instances of emergence of public clonotypes specific for CMV or EBV that were not detected before DLI were seen in virus-positive patients whose donors were virus-negative. Emergence and rapid expansion of donor-derived clonotypes to frequencies up to 6.75% suggests that naïve T cells present in the DLI had been primed upon encounter with virus in the patient. In vitro stimulation with overlapping 15-mer peptide libraries for CMV antigens and EBV antigens followed by assessment of activation marker expression and interferon-γ, MIP-1β, and TNF-α production showed that virus-specific T-cell responses increased in magnitude and poly-functionality after DLI. These findings show that DLI replenishes naïve T cells and restores ability to respond to viral antigens previously unseen. By inference, this may extend to leukaemia antigens and underlie the reduced rate of malignant disease relapse seen in patients given pDLI. Disclosures No relevant conflicts of interest to declare.

scholarly journals One naive T cell, multiple fates in CD8+ T cell differentiation

2010 ◽  
Vol 207 (6) ◽  
pp. 1235-1246 ◽  
Author(s):  
Carmen Gerlach ◽  
Jeroen W.J. van Heijst ◽  
Erwin Swart ◽  
Daoud Sie ◽  
Nicola Armstrong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Large Scale ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
High Avidity ◽  
Naive T Cells ◽  
Memory T Cell ◽  
Naïve T Cells ◽  
Large Scale Assessment

The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcodes present in antigen-specific effector and memory T cell populations in systemic and local infection models, at different anatomical sites, and for TCR–pMHC interactions of different avidities, we demonstrate that under all conditions tested, individual naive T cells yield both effector and memory CD8+ T cell progeny. This indicates that effector and memory fate decisions are not determined by the nature of the priming antigen-presenting cell or the time of T cell priming. Instead, for both low and high avidity T cells, individual naive T cells have multiple fates and can differentiate into effector and memory T cell subsets.

scholarly journals Induction of memory-like CD8 + T cells and CD4 + T cells from human naïve T cells in culture

2021 ◽  
Author(s):  
Yasuhito Tokumoto ◽  
Yasuto Araki ◽  
Yusuke Narizuka ◽  
Yosuke Mizuno ◽  
Susumu Ohshima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Quiescent State ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cells In Culture ◽  
Human T Cells

Abstract Memory T cells are crucial players in vertebrate adaptive immunity but their development is incompletely understood. Here we describe a method to produce human memory-like T cells from naïve human T cells in culture. Using commercially available human T cell differentiation kits, both purified naïve CD8 + T cells and purified naïve CD4 + T cells were activated via T cell receptor signaling and appropriate cytokines for several days in culture. All the T cell activators were then removed from the medium and the cultures were continued in hypoxic condition (1% O2 atmosphere) for several more days; during this period, most of the cells died, but some survived in a quiescent state for a month. The survivors had small round cell bodies, expressed differentiation markers characteristic of memory T cells and restarted proliferation when the T cell activators were added back. We could also induce memory-like T cells from naïve human T cells without hypoxia, if we froze the activated T cells or prepared the naïve T cells from chilled filter buffy coats.

scholarly journals Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

2021 ◽  
Author(s):  
Joy A. Pai ◽  
Andrew Chow ◽  
Jennifer Sauter ◽  
Marissa Mattar ◽  
Hira Rizvi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd8 T Cell ◽  
Immune Checkpoint Blockade ◽  
Rna Seq ◽  
Cell Dynamics ◽  
T Cell Clones ◽  
Cell Clones

Paired T cell receptor and RNA single cell sequencing (scTCR/RNA-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scTCR/RNA-seq dataset of 162,062 single T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients who underwent resections for progressing lung cancers after immune checkpoint blockade (ICB). We found marked regional heterogeneity in tumor persistence that was associated with heterogeneity in CD4 and CD8 T cell phenotypes; regions with persistent cancer cells were enriched for follicular helper CD4 T cells (TFH), regulatory T cells (Treg), and exhausted CD8 T cells. Clonal analysis demonstrated that highly-expanded T cell clones were predominantly of the CD8 subtype, were ubiquitously present across all sampled regions, found in the peripheral circulation, and expressed gene signatures of 'large' and 'dual-expanded' clones that have been predictive of response to ICB. Longitudinal tracking of CD8 T cell clones in the peripheral blood revealed that the persistence of ubiquitous CD8 T cell clones, as well as phenotypically distinct clones with tumor-reactive features, correlated with systemic tumor control. Finally, tracking CD8 T cell clones across tissues revealed the presence of TCF-1+ precursor exhausted CD8 T cells in tumor draining LNs that were clonally linked to expanded exhausted CD8 T cells in tumors. Altogether, this comprehensive scTCR/RNA-seq dataset with regional, longitudinal, and clonal resolution provides fundamental insights into the tissue distribution, persistence, and differentiation trajectories of ICB-responsive T cells that underlie clinical responses to ICB.

Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2860-2868 ◽  
Author(s):  
Francesco F. Fagnoni ◽  
Rosanna Vescovini ◽  
Giovanni Passeri ◽  
Giovanni Bologna ◽  
Mario Pedrazzoni ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Life Span ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Lymphocyte Count ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naive T Cell

Clinical observations indicate that elderly people are prone to severe, often lethal infectious diseases induced by novel pathogens. Since the ability to mount primary immune responses relies on the availability of naive T cells, the circulating naive T-cell reservoir was evaluated throughout the human life span. Naive T cells were identified as CD95− T lymphocytes for their phenotypic and functional features. Indeed, the lack of CD95 marker is sufficient to identify a population of naive T cells, as defined by coincidence with previously characterized CD45RA+ CD62L+ T cells. Naive CD95− T cells, as expected, require a costimulatory signal, such as CD28, to optimally proliferate after anti-CD3 stimulation. Cytofluorimetric analysis of circulating T lymphocytes from 120 healthy subjects ranging in age from 18 to 105 years revealed that naive T cells decreased sharply with age. The younger subjects had a naive T-lymphocyte count of 825 ± 48 cells/μL, and the centenarians had a naive T-lymphocyte count of 177 ± 28 cells/μL. Surprisingly, the naive T-cell count was lower in CD8+than in CD4+ subsets at any age, and the oldest individuals were almost completely depleted of circulating naive CD8+ T cells (13 ± 4 cells/μL). Concomitantly, a progressive expansion of CD28− T cells occurs with age, which can be interpreted as a compensatory mechanism. These data provide new insights into age-related T-cell–mediated immunodeficiency and reveal some analogies of T-cell dynamics between advanced aging and human immunodeficiency virus (HIV) infection. In conclusion, the exhaustion of the naive CD8+ T-cell reservoir, which has never been reported before, suggests that this T-cell pool is a major target of the aging process and may define a parameter possibly related to the life span of humans.

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Membrane Filter ◽  
Cd8 T Cell ◽  
Class I ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

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