The Hayflick Limit and Age-Related Adaptive Immune Deficiency

Gerontology ◽  
2017 ◽  
Vol 64 (2) ◽  
pp. 135-139 ◽  
Author(s):  
Zoe Gill ◽  
Martin Nieuwoudt ◽  
Wilfred Ndifon
Keyword(s):  
Immune Deficiency ◽  
T Cells ◽  
T Cell ◽  
Older Individuals ◽  
Adaptive Immune ◽  
Hayflick Limit ◽  
Age Related ◽  
Cell Diversity ◽  
Naïve T Cell ◽  
Naive T Cell

The adaptive immune system (AIS) acquires significant deficiency during chronological ageing, making older individuals more susceptible to infections and less responsive to vaccines compared to younger individuals. At the cellular level, one of the most striking features of this ageing-related immune deficiency is the dramatic loss of T-cell diversity that occurs in elderly humans. After the age of 70 years, there is a sharp decline in the diversity of naïve T cells, including a >10-fold decrease in the CD4+ compartment and a >100-fold decrease in the CD8+ compartment. Such changes are detrimental because the AIS relies on a diverse naïve T-cell pool to respond to novel pathogens. Recent work suggests that this collapse of naïve T-cell diversity results from T cells reaching the Hayflick limit and being eliminated through both antigen-dependent and -independent pathways. The progressive attrition of telomeres is the molecular mechanism that underlies this Hayflick limit. Therefore, we propose that by measuring the telomere lengths of T cells with high resolution, it is possible to develop a unique biomarker of immune deficiency, potentially much better correlated with individual susceptibility to diseases compared to chronological age alone.

scholarly journals Cell generation dynamics underlying naïve T cell homeostasis in adult humans

2019 ◽  
Author(s):  
Jeff E. Mold ◽  
Pedro Réu ◽  
Axel Olin ◽  
Samuel Bernard ◽  
Jakob Michaëlsson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Turnover ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Age Related ◽  
Cell Clones ◽  
Naïve T Cell ◽  
Cd31 Expression ◽  
Naive T Cell

ABSTRACTThymic involution and proliferation of naive T cells both contribute to shaping the naive T cell repertoire as humans age, but a clear understanding of the roles of each throughout a human lifespan has been difficult to determine. By measuring nuclear bomb test-derived14C in genomic DNA we determined the turnover rates of CD4+and CD8+naïve T cell populations and defined their dynamics in healthy individuals ranging from 20-65 years of age. We demonstrate that naïve T cell generation decreases with age, and that this could be explained by a combination of declining cell loss, peripheral division and thymic production during adulthood. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of naïve T cell turnover using mass cytometry to profile candidate signaling pathways involved in T cell activation and proliferation in CD4+naive T cells relative to CD31 expression, a marker of thymic proximity. We show that basal NF-κB phosphorylation inversely correlated with CD31 expression and thus is decreased in peripherally expanded naive T cell clones. Functionally we found that NF-κB signaling was essential for naive T cell proliferation to the homeostatic growth factor IL-7, and reduced NF-κB phosphorylation in CD4+CD31−naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naïve T cell turnover as a putative regulator of naïve T cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T cell clones that accumulate with age.

scholarly journals VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Science ◽  
2020 ◽  
Vol 367 (6475) ◽  
pp. eaay0524 ◽  
Author(s):  
Mohamed A. ElTanbouly ◽  
Yanding Zhao ◽  
Elizabeth Nowak ◽  
Jiannan Li ◽  
Evelien Schaafsma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Subset ◽  
Peripheral Tolerance ◽  
Cell Immune Response ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

The lymphoid chemokine CCL21 costimulates naïve T cell expansion and Th1 polarization of non-regulatory CD4+ T cells

2004 ◽  
Vol 231 (1-2) ◽  
pp. 75-84 ◽  
Author(s):  
Kenneth Flanagan ◽  
Dorota Moroziewicz ◽  
Heesun Kwak ◽  
Heidi Hörig ◽  
Howard L. Kaufman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Expansion ◽  
T Cell Expansion ◽  
Th1 Polarization ◽  
Naïve T Cell ◽  
Naive T Cell

CMVpp65-Specific T cells generated from naïve T cell populations recognize atypical but not canonical epitopes and may be protective in Vivo

Cytotherapy ◽  
2015 ◽  
Vol 17 (6) ◽  
pp. S9-S10
Author(s):  
Patrick Hanley ◽  
Joseph Melenhorst ◽  
Russell Cruz ◽  
Caridad Martinez ◽  
Helen Heslop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Populations ◽  
Naïve T Cell ◽  
Naive T Cell

scholarly journals Naive T-cell receptor transgenic T cells help memory B cells produce antibody

Immunology ◽  
2006 ◽  
Vol 119 (3) ◽  
pp. 376-384 ◽  
Author(s):  
Darragh Duffy ◽  
Chun-Ping Yang ◽  
Andrew Heath ◽  
Paul Garside ◽  
Eric B. Bell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Memory B Cells ◽  
Naïve T Cell ◽  
Naive T Cell

Interleukin-7–treated naive T cells can be productively infected by T-cell–adapted and primary isolates of human immunodeficiency virus 1

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3310-3318 ◽  
Author(s):  
Carolyn M. Steffens ◽  
Elizabeth Z. Managlia ◽  
Alan Landay ◽  
Lena Al-Harthi
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Productive Infection ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Although human immunodeficiency virus (HIV)gag/pol DNA can be detected in naive T cells, whether naive T cells can be productively infected by HIV is still questionable. Given that interleukin-7 (IL-7) is a prospective therapeutic immunomodulator for the treatment of HIV, we evaluated the effect of IL-7 on promoting naive T-cell infection of laboratory-adapted (IIIB), M-tropic, and primary isolates of HIV. Initially, we determined that the 3 cell surface markers widely used to identify naive T cells (CD45RA+CD45RO−, CD45RA+CD62L+, and CD45RO−CD27+CD95low) are all equivalent in T-cell receptor excision circle content, a marker for the replicative history of a cell as well as for de novo T cells. We therefore used CD45RA+CD45RO− expression to define naive T cells in this study. We demonstrate that although untreated or IL-2–treated naive T cells are not productively infected by HIV, IL-7 pretreatment mediated the productive infection of laboratory-adapted, M-tropic, and primary isolates of HIV as determined by p24 core antigen production. This up-regulation was between 8- and 58-fold, depending on the HIV isolate used. IL-7 pretreatment of naive T cells also potently up-regulated surface expression of CXCR4 but not CCR5 and mediated the expansion of naive T cells without the acquisition of the primed CD45RO phenotype. Collectively, these data indicate that IL-7 augments naive T-cell susceptibility to HIV and that under the appropriate environmental milieu, naive T cells may be a source of HIV productive infection. This information needs to be considered in evaluating IL-7 as an immunomodulator for HIV-infected patients.

Ex Vivo Fludarabine Selectively Depletes Human Naive T-Cell Subsets: A Step Toward Modifying Donor Lymphocyte Infusion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1071-1071
Author(s):  
Melody M. Smith ◽  
Cynthia R. Giver ◽  
Edmund K. Waller ◽  
Christopher R. Flowers
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Ex vivo modification of donor lymphocytes with purine analogs (mDL) may help to minimize graft versus host disease (GvHD) while providing beneficial graft versus leukemia (GvL) effects. In a murine model system, we have shown that allogeneic donor splenocytes, treated with fludarabine ex vivo have significantly reduced GvHD activity when transferred to irradiated recipient mice, and retain anti-viral and GvL activities (Giver, 2003). This effect appears to be mediated by relative depletion of donor CD4 CD44low, “naive” T-cells. As a first step toward developing mDL for use in patients, we sought to evaluate the effects of ex vivo fludarabine exposure on human T-cell subsets, and to determine the minimum dose of fludarabine required to achieve this effect. Methods: Peripheral blood mononuclear cell samples from 6 healthy volunteers were evaluated at 0, 24, 48, and 72 hour time points after ex vivo incubation in varying dosages of fludarabine: 2, 5, and 10(n=3) mcg/ml. Fludarabine incubated samples were compared to samples that received no fludarabine (untreated). The total viable cell number was determined and the fractions and absolute numbers of viable CD4 and CD8 naïve and memory T-cells were determined using flow cytometry after incubation with 7-AAD (dead cell stain), CD4, CD8, CD45RA, CD62L, and CCR7 antibodies, and measuring the total viable cells/ml. Results: The numbers of viable CD4 and CD8 T-cells remained relatively stable in control cultures. Without fludarabine, the average viability at 72 hr of naive and memory T-cells were 92% and 77% for CD4 and 86% and 63% for CD 8 (Fig. 1A). Naive CD4 T-cells were more sensitive to fludarabine-induced death than memory CD4 cells. At 72 hr, the average viability of fludarabine-treated naive CD4 T-cells was 33% at 2 mcg/ml (8.2X the reduction observed in untreated cells) and 30% at 5 mcg/ml, while memory CD4 T-cells averaged 47% viability at 2 mcg/ml (2.3X the reduction observed in untreated cells) (Fig. 1B) and 38% at 5 mcg/ml. The average viability of naive CD8 T-cells at 72 hr was 27% at 2 mcg/ml and 20% at 5 mcg/ml, while memory CD8 T-cell viability was 22% at 2 mcg/ml and 17% at 5 mcg/ml. Analyses on central memory, effector memory, and Temra T-cells, and B-cell and dendritic cell subsets are ongoing. The 5 and 10 mcg/ml doses also yielded similar results in 3 initial subjects, suggesting that 2 mcg/ml or a lower dose of fludarabine is sufficient to achieve relative depletion of the naive T-cell subset. Conclusions: Future work will determine the minimal dose of fludarabine to achieve this effect, test the feasibility of using ex vivo nucleoside analog incubation to reduce alloreactivity in samples from patient/donor pairs, and determine the maximum tolerated dose of mDL in a phase 1 clinical trial with patients at high risk for relapse and infectious complications following allogeneic transplantation. Figure Figure

scholarly journals Frequencies of FoxP3+ naïve T cells are related to both viral load and naïve T cell proliferation responses in HIV disease

2011 ◽  
Vol 90 (3) ◽  
pp. 621-628 ◽  
Author(s):  
Benigno Rodriguez ◽  
Douglas A. Bazdar ◽  
Nicholas Funderburg ◽  
Robert Asaad ◽  
Angel A. Luciano ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
T Cell Proliferation ◽  
Hiv Disease ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

scholarly journals Tracking SARS-CoV-2 T cells with epitope-T-cell receptor recognition models

2020 ◽  
Author(s):  
Pieter Meysman ◽  
Anna Postovskaya ◽  
Nicolas De Neuter ◽  
Benson Ogunjimi ◽  
Kris Laukens
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Sequencing Data ◽  
Adaptive Immune ◽  
Cell Diversity ◽  
Longitudinal Profiles

Much is still not understood about the human adaptive immune response to SARS-CoV-2, the causative agent of COVID-19. In this paper, we demonstrate the use of machine learning to classify SARS-CoV-2 epitope specific T-cell clonotypes in T-cell receptor (TCR) sequencing data. We apply these models to public TCR data and show how they can be used to study T-cell longitudinal profiles in COVID-19 patients to characterize how the adaptive immune system reacts to the SARS-CoV-2 virus. Our findings confirm prior knowledge that SARS-CoV-2 reactive T-cell diversity increases over the course of disease progression. However our results show a difference between those T cells that react to epitope unique to SARS-CoV-2, which show a more prominent increase, and those T cells that react to epitopes common to other coronaviruses, which begin at a higher baseline.

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