scholarly journals The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection

2022 ◽  
Author(s):  
Nadia Anikeeva ◽  
Maria Steblyanko ◽  
Leticia Kuri-Cervantes ◽  
Marcus Buggert ◽  
Michael R Betts ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Lipid Bilayers ◽  
Cd8 T Cells ◽  
Premature Aging ◽  
Low Grade ◽  
Naive T Cells ◽  
Infected People ◽  
Naïve T Cells ◽  
Chronic Hiv 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.

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 CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection

2019 ◽  
Vol 15 (8) ◽  
pp. e1007970 ◽  
Author(s):  
Kai Qin ◽  
Sushma Boppana ◽  
Victor Y. Du ◽  
Jonathan M. Carlson ◽  
Ling Yue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Dendritic Cell Maturation ◽  
Cd4 T Cell ◽  
Cell Maturation ◽  
Trans Infection ◽  
Chronic Hiv Infection

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

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

Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 4928-4938 ◽  
Author(s):  
Patricia Ribeiro-dos-Santos ◽  
Emma L. Turnbull ◽  
Marta Monteiro ◽  
Agnès Legrand ◽  
Karen Conrod ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cell Functions ◽  
Chronic Hiv Infection

Abstract CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T-cell functions, “exhausted” lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-γ but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up-regulating Eomesodermin expression.

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.

DEFICIT DEEPENING OF NAIVE T-CELLS CD4+ IN PATIENTS WITH HIV INFECTION WHEN CO-INFECTED WITH HEPATITIS C VIRUS

2018 ◽  
Vol 4 ◽  
pp. 15-19
Author(s):  
K.V. Shmagel ◽  
◽  
L.B. Korolevskaya ◽  
E.V. Saydakova ◽  
N.G. Shmagel ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hiv Infection ◽  
Naive T Cells ◽  
Naïve T Cells

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 The Immune Synapses Reveal Aberrant Functions of Cd8 T Cells During Chronic HIV Infection

2021 ◽  
Author(s):  
Nadia Anikeeva ◽  
Maria Steblyanko ◽  
Leticia Kuri Cervantes ◽  
Marcus Buggert ◽  
Michael R. Betts ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Immune Synapses ◽  
Chronic Hiv Infection

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

Hypertension ◽  
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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