Faculty Opinions recommendation of Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection.

It is well-established that chronic HIV infection causes persistent low-grade inflammation that induces premature aging of the immune system in HIV patient including senescence of memory and effector CD8 T cells. To uncover the reasons of gradually diminished potency of CD8 T cells from chronically HIV infected people, we have analyzed cellular morphology and dynamics of the synaptic interface followed exposure of peripheral polyclonal CD8 T cells at various differentiation stages to planar lipid bilayers. The above parameters were linked to pattern of degranulation that determines efficiency of CD8 T cells cytolytic response. We found a large fraction of naive T cells from HIV infected people developing mature synapses and demonstrating focused degranulation, a signature of a differentiated T cells. Further differentiation of aberrant naive T cells leads to development of anomalous effector T cells undermining their capacity to control HIV and other viruses that could be contained otherwise.

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

Blood ◽

10.1182/blood.v128.22.2233.2233 ◽

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.

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CD27BRIGHT CD45RABRIGHT CD8 T Cells Expressing EOMES, T-BET and HOBIT: Naïve T Cells Losing Innocence?

Transplantation Journal ◽

10.1097/00007890-201407151-01014 ◽

2014 ◽

Vol 98 ◽

pp. 319

Author(s):

E. Remmerswaal ◽

M. van Aalderen ◽

N. van der Bom-Baylon ◽

K. van Donselaar-van der Pan ◽

F. Bemelman ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Naive T Cells ◽

Naïve T Cells

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Cortisol and epinephrine control opposing circadian rhythms in T cell subsets

Blood ◽

10.1182/blood-2008-11-190769 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5134-5143 ◽

Cited By ~ 172

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.

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

Clinical & Experimental Immunology ◽

10.1093/cei/uxab012 ◽

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.

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Abstract 002: Adoptive Transfer of CD8 T Cells With Constitutively Active Pi3kγ Induces Hypertension in Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.002 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Daniela Carnevale ◽

Maria Piacenti ◽

Giuseppe Cifelli ◽

Roberta Iacobucci ◽

Giuseppe Lembo

Keyword(s):

Blood Pressure ◽

T Cells ◽

Renal Function ◽

Cd8 T Cells ◽

Adoptive Transfer ◽

Intracellular Signaling ◽

Effector T Cells ◽

Naive T Cells ◽

Naïve T Cells ◽

Constitutively Active

In the field of research exploring the connection existing between hypertension and immune system, CD8 effector T cells emerge as the possible mediators of target organ colonization. In the absence of overt inflammation or pathogen response, naïve T cells circulate from the blood into secondary lymphoid organs, where, upon challenge, become activated. Then, they differentiate into effector T cells, which display typical activation patterns. However, less is known about the intracellular signaling pathways that are responsible for the acquisition of effectors functions in T cells. The p110γ isoform of the PI3K family has unique features, being crucially involved in the immune and cardiovascular systems. On this issue, we have described that PI3Kγ has a crucial role in blood pressure regulation, being KO mice protected from AngII-induced hypertension. Moreover, we found that mice with a constitutively active PI3Kγ isoform (CAAX mice) were spontaneously hypertensive (SBP: CAAX 135 ± 3 vs WT 105 ± 4 mmHg, p<0.001). Interestingly, PI3Kγ is known to play a selective role in regulating the migration of effector CD8 T cells, even though there was no effect of PI3Kγ in naïve T cells. Thus we explored the possible involvement of PI3Kγ in the crosstalk between hypertension and immunity. CAAX mice displayed a significant infiltration of activated CD8 + CD69 + T cells in kidney, as compared to WT mice (10.2 ± 2.1 vs 2.8 ± 0.6 *10 4 cells/kidney, p<0.01). At the functional level, this phenotype was associated with enlarged Bowman’s spaces and fibrosis in the kidney of CAAX mice, leading to disruption of renal function, as shown by later development of proteinuria. In the end, to demonstrate whether the CAAX hypertensive phenotype, associated to renal damage after CD8 colonization, could be ascribed to the overactivation of PI3Kγ signaling in this immune cell type, we performed an adoptive transfer of CD8 T cells isolated from CAAX mice in WT mice. Strikingly we found that CD8 T cells with constitutively active PI3Kγ were effective to induce hypertension in naïve mice. These data suggest that in the development of hypertension, PI3Kγ signaling in CD8 T cells is crucial for their accumulation in the kidney, likely contributing to increase in blood pressure by altering renal function.

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Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation

Journal of Experimental Medicine ◽

10.1084/jem.20131271 ◽

2014 ◽

Vol 211 (2) ◽

pp. 345-356 ◽

Cited By ~ 62

Author(s):

Erin R. Mehlhop-Williams ◽

Michael J. Bevan

Keyword(s):

Cell Cycle ◽

T Cells ◽

Cd8 T Cells ◽

Memory T Cells ◽

Protein Tyrosine Phosphatases ◽

Central Memory ◽

Naive T Cells ◽

Memory Cd8 T Cells ◽

Naïve T Cells

A hallmark of immunological memory is the ability of previously primed T cells to undergo rapid recall responses upon antigen reencounter. Classic work has suggested that memory T cells proliferate in response to lower doses of antigen than naive T cells and with reduced requirements for co-stimulation. In contrast to this premise, we observed that naive but not memory T cells proliferate in vivo in response to limited antigen presentation. To reconcile these observations, we tested the antigen threshold requirement for cell cycle entry in naive and central memory CD8+ T cells. Although both naive and memory T cells detect low dose antigen, only naive T cells activate cell cycle effectors. Direct comparison of TCR signaling on a single cell basis indicated that central memory T cells do not activate Zap70, induce cMyc expression, or degrade p27 in response to antigen levels that activate these functions in naive T cells. The reduced sensitivity of memory T cells may result from both decreased surface TCR expression and increased expression of protein tyrosine phosphatases as compared with naive T cells. Our data describe a novel aspect of memory T cell antigen threshold sensitivity that may critically regulate recall expansion.

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CXCL12 Mediates CCR7-independent Homing of Central Memory Cells, But Not Naive T Cells, in Peripheral Lymph Nodes

Journal of Experimental Medicine ◽

10.1084/jem.20031645 ◽

2004 ◽

Vol 199 (8) ◽

pp. 1113-1120 ◽

Cited By ~ 83

Author(s):

M. Lucila Scimone ◽

Thomas W. Felbinger ◽

Irina B. Mazo ◽

Jens V. Stein ◽

Ulrich H. von Andrian ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Cd8 T Cells ◽

Lymphoid Organs ◽

Central Memory ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells ◽

Peripheral Lymph ◽

Secondary Lymphoid Organs

Central memory CD8+ T cells (TCM) confer superior protective immunity against infections compared with other T cell subsets. TCM recirculate mainly through secondary lymphoid organs, including peripheral lymph nodes (PLNs). Here, we report that TCM, unlike naive T cells, can home to PLNs in both a CCR7-dependent and -independent manner. Homing experiments in paucity of lymph node T cells (plt/plt) mice, which do not express CCR7 ligands in secondary lymphoid organs, revealed that TCM migrate to PLNs at ∼20% of wild-type (WT) levels, whereas homing of naive T cells was reduced by 95%. Accordingly, a large fraction of endogenous CD8+ T cells in plt/plt PLNs displayed a TCM phenotype. Intravital microscopy of plt/plt subiliac lymph nodes showed that TCM rolled and firmly adhered (sticking) in high endothelial venules (HEVs), whereas naive T cells were incapable of sticking. Sticking of TCM in plt/plt HEVs was pertussis toxin sensitive and was blocked by anti-CXCL12 (SDF-1α). Anti-CXCL12 also reduced homing of TCM to PLNs in WT animals by 20%, indicating a nonredundant role for this chemokine in the presence of physiologic CCR7 agonists. Together, these data distinguish naive T cells from TCM, whereby only the latter display greater migratory flexibility by virtue of their increased responsiveness to both CCR7 ligands and CXCL12 during homing to PLN.

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

10.1101/2022.01.07.475400 ◽

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.

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

Blood ◽

10.1182/blood.v95.9.2860.009k35_2860_2868 ◽

2000 ◽

Vol 95 (9) ◽

pp. 2860-2868 ◽

Cited By ~ 344

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.

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