Immunosenescence of Lymphocytes T and Implications for Age-Related Disorders

2020 ◽  
Author(s):  
Anna Tylutka ◽  
Barbara Morawin ◽  
Artur Gramacki ◽  
Agnieszka Zembron-Lacny
Keyword(s):  
T Cells ◽  
Elderly People ◽  
Cd8 T Cells ◽  
The Elderly ◽  
Health Concern ◽  
Female Group ◽  
Major Health ◽  
Cd8 Cells ◽  
Age Related ◽  
Sex Disorders

Abstract Background. The decrease in immunity with age is still a major health concern as elderly people are more susceptible to infections and increased incidence of autoimmunity. Consequently, there is an increasing interest in immunosenescence and changes in immunology cells like T cells. The aim of our study was to find a disproportion in subpopulation of T cells as well as CD4/CD8 ratio depending on the age, gender or comorbidities. Results. In the present study, a flow cytometry was used to indicate the differences between age, sex, disorders and fat content in the CD4+ and CD8+ T cells population divided into naïve and memory cells as well as CD4/CD8 ratio in people aged 71.9± 5.8 years (females n=83, males n=16) compared to young people aged 20.6 ± 1.1 years (females n=12, males n=19). The percentage of naïve CD4+ and CD8+ cells was found to be statistically significantly lower in the elderly compared to the young. In addition, gender was observed to play an important role in the outcomes in the analysed subpopulations and in female group, who live statistically longer than males, our older group of Polish women demonstrated a significantly higher percentage of naïve lymphocytes in both the CD4+ and CD8+ populations compared to men. The CD4/CD8 ratio increases with age, which can be considered one of the markers determining longevity. Elderly people with age-related diseases (hypertension) also show an increased level of CD4/CD8 ratio as well as CD4+. Conclusion. We demonstrated that changes in the T cells population, including naïve cell population as well as CD4/CD8 ratio, are important markers which can be predictive of healthy status. In order to accurately determine longevity, gender or age-associated diseases should be taken into account.

scholarly journals Key role of T cell defects in age-related vulnerability to West Nile virus

2009 ◽  
Vol 206 (12) ◽  
pp. 2735-2745 ◽  
Author(s):  
James D. Brien ◽  
Jennifer L. Uhrlaub ◽  
Alec Hirsch ◽  
Clayton A. Wiley ◽  
Janko Nikolich-Žugich
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
T Cell ◽  
Cd8 T Cells ◽  
The Elderly ◽  
T Cell Response ◽  
West Nile ◽  
Immunodeficient Mice ◽  
Age Related ◽  
Cell Immunity

West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50× more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12× fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

Probabilistic Prediction of Microdamage Progression in Bone

2008 ◽  
Author(s):  
X. Neil Dong ◽  
Daniel M. Sparkman ◽  
Huijie Leng ◽  
Harry R. Millwater ◽  
Xiaodu Wang
Keyword(s):  
Bone Quality ◽  
Elderly Population ◽  
Bone Fractures ◽  
The Elderly ◽  
Ultrastructural Level ◽  
Optical Microscope ◽  
Health Concern ◽  
Probabilistic Prediction ◽  
Major Health ◽  
Age Related

Age-related bone fractures are a major health concern to the elderly population. In addition to the loss of bone mass, the deterioration of bone quality is another major reason for such fractures. The decline of bone quality is manifested with the accumulation of microdamage in bone with age [1]. Two major types of microdamage have been observed in bone tissue: linear microcracks and diffuse damage [2]. Linear microcracks are individual cracks at a size of microns or larger and are usually visible under an optical microscope. On the other hand, diffuse damage is detectable only by staining and consists of an extensive network of fine, ultrastructural-level defects. The mechanisms for the formation of these two distinct types of microdamage in bone are still unclear. In this study, probabilistic finite element models of mineral-collagen composites were used to study the progression of microdamage in bone, thereby exploring the conditions under which linear microcracks and diffuse damage are produced in bone.

Age-related differences in T cell subsets in a nationally representative sample of people over age 55: Findings from the Health and Retirement Study

2021 ◽  
Author(s):  
Bharat Thyagarajan ◽  
Jessica Faul ◽  
Sithara Vivek ◽  
Jung Ki Kim ◽  
Janko Nikolich-Žugich ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Subsets ◽  
Health And Retirement Study ◽  
Cd8 Cells ◽  
Age Related ◽  
Nationally Representative ◽  
Retirement Study ◽  
Age And Sex

Abstract Though T cell immunosenescence is a major risk factor for age-related diseases, susceptibility to infections, and responses to vaccines, differences in T cells subset counts and representation by age and sex have not been determined for a large sample representative of the national population of the US. We evaluated the counts of T cell subsets including total, CD4+ and CD8+ T cells, and their naïve (Tn), effector memory (Tem) and effector subsets, in the context of age, sex and exposure to cytomegalovirus (CMV) infection among 8,848 Health and Retirement Study (HRS) participants, a nationally representative study of adults over 55 years. Total T cells (CD3+) and CD4+ cells declined markedly with age; CD8+ T cells declined somewhat less. While CD4+ T cell declines with age occurred for both CMV seropositive and CMV seronegative groups, total T cells and CD8+ cells were both substantially higher among the CMV seropositive group. Numbers of Tn CD4+ and CD8+ cells were strongly and inversely related to age, were better conserved among women, and were independent of CMV seropositivity. By contrast, accumulation of the CD8+ and CD4+ Tem and effector subsets was CMV-associated. This is the first study to provide counts of T cell subsets by age and sex in a national sample of older US adults over the age of 55 years. Understanding T cell changes with age and sex is an important first step in determining strategies to reduce its impact on age-related diseases and susceptibility to infection.

Age-Related Decrease of Human CD8+ T-Cell Mir-92a Level Correlated with Reduction of naïve T Lymphocyte

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2186-2186
Author(s):  
Michiyo Ohyashiki ◽  
Junko H Ohyashiki ◽  
Ayako Hirota ◽  
Chiaki Kobayashi ◽  
Kazuma Ohyashiki
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Cd8 T Cell ◽  
Expression Level ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Age Related ◽  
Significant Difference

Abstract Abstract 2186 Background and Aim: MicroRNAs (miRNAs) consist of short noncoding RNA molecules of approximately 18–22 nucleotide that regulate post-transcriptional gene expression by degradation or repression of mRNA molecules. The miR-17-92a cluster is known as a regulator of the immune system and is critical for lymphoid cellular development and tumorigenesis in lymphoid tissue. Most knowledge of the miR-17-92 cluster in normal and abnormal conditions of the lymphoid system is based on mouse experiments. It is suggested that the accumulation of activated CD4+ T cells by higher mir-17-92 expression leads to a breakdown of T-cell tolerance in the periphery and may promote B-cell activation, germinal center reaction and autoantibody generation. However, only limited reports on in vivo human lymphocyte senescence exist. We therefore set out to determine miR-92a levels in circulating lymphocytes obtained from healthy participants to ascertain the possible association between immunological condition and the expression level of miR-17-92. Experimental design: We separated lymphocytes from 21 healthy volunteers, aged 23 to 58 years (13 men and 8 women), for surface marker and miR-92a level analyses. The CD4+ or CD8+ T-cell fractions were separated with an isolation kit for humans (Miltenyi Biotec, Bergisch Gladbach, Germany) and AutoMACS Pro Separator (Miltenyi Biotec), according to the supplier's instruction, and stored at −80°C until utilization. After separation of CD4+ or CD8+ cells, the miR-92a levels were measure, as reported previously (PLoS ONE. 2011, 24;6(2);e16408). Immunophenotyping was done with flow cytometry. Results: The miR-92a of separated CD8+ lymphocytes decreased significantly with age (P = 0.0002), and miR-92a in CD4+ cells tended to decrease with age (P = 0.0635). We found a positive correlation between CD8+ miR-92a expression level and the percentage of naive CD8+ T cells (RO−CD8+CD27+ cells (P = 0.0046)) with L-selectin antigen (CD3+CD8+CD62L+ (P = 0.0011)) in healthy subjects. This suggests that the miR-92a of a majority of CD8+ T is derived from naive CD8+ T cells with L-selectin antigen, and CD8+ miR-92a expression level declines progressively with age (P < 0.0001 and P < 0.0001, respectively). In CD4+ cells, we observed a trend of decreasing CD4+ miR-92a level with age, while no significant difference was notable with lymphocyte subset fraction as far as we tested. The index of CD8+ miR-92a values (CD8+ miR-92a×number of CD8 cells) was positively correlated with the index of CD4+ miR-92a values (P = 0.0101). Discussion: These results indicate an age-related reduction of naive T cells may link to miR-92a of T-lymphocytes and may influence immune dysfuction with age. In conclusion, our results suggest that the miR-92a level may represent attrition of naïve CD8+ T cells, possibly due to apoptosis of naïve T cells. Additionally down-regulation of the miR-92a level in individuals older than 40 years may indicate impairment or exhaustion of naïve T-cells linked to immune dysfunction and contributed disease states. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pro-inflammatory CD8 T Cells Contribute to Age-Related Large Artery Stiffening

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 134-134
Author(s):  
Daniel Trott ◽  
Sunita Sharma
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cd8 T Cells ◽  
Large Artery ◽  
Cd8 Cells ◽  
Age Related ◽  
Tnf Α ◽  
Artery Stiffness ◽  
Ifn Γ ◽  
Old Mice

Abstract We have shown that T cells accumulate around the aorta with advanced age and that both pharmacologic and genetic deletion of total T cells result in improved large artery stiffness in old mice. The purpose of this study was to test the hypothesis that CD8 T cells specifically mediate age-related large artery stiffening. We randomized old (22-24 month) C57Bl6 mice (n=5/group) to treatment with an anti-CD8 or isotype control antibody (100µg every 5 days) for 28 days. We assessed large artery stiffness using pulse wave velocity (PWV) before and after antibody treatment. We found that PWV was similar between isotype (301±14 cm/s) and anti-CD8 (292±18 cm/s) before treatment. Following treatment, anti-CD8 treated mice exhibited lower PWV (272±11 cm/s) compared to the isotype (315±14 cm/s). Following euthanasia, we assessed aortic T cell infiltration by flow cytometry we found that anti-CD8 treated mice exhibited blunted aortic total CD3+ (262±42 vs. 1400±94 cells per aorta) and CD8+ (52±19 vs. 565±139 cells per aorta) cells compared to isotype controls. In a separate cohort of mice we compared interferon (IFN)-γ and tumor necrosis factor (TNF)-α production of aortic infiltrating CD8 cells from young (4-6 months, n=5) and old mice (n=8) using flow cytometry. A greater proportion of CD8 cells from old aortas produced IFN-γ (70±3% vs. 46±6%) compared to young. Similarly, a greater proportion of aortic infiltrating CD8 cells from old mice produced TNF-α (35±6% vs. 17±3%) compared to young. Collectively, these results suggest that pro-inflammatory CD8 cells contribute to cell non-autonomous arterial aging.

scholarly journals EXTH-14. A NOVEL LONG-ACTING INTERLEUKIN-7 AGONIST, NT-I7, INCREASES CYTOTOXIC CD8 CELLS AND ENHANCES SURVIVAL IN MOUSE GLIOMA MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii89-ii89
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting ◽  
Spleen And Lymph Nodes ◽  
Mouse Glioma

Abstract BACKGROUND Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival. METHODS C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. RESULTS Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p&lt; 0.0021; CT2A: 90d vs 40d, p&lt; 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p&lt; 0.008; CT2A: 90d vs 32d, p&lt; 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment. CONCLUSIONS NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

565 A novel long-acting interleukin-7 agonist, NT-I7, increases cytotoxic CD8+ T cells and enhances survival in mouse glioma models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A599-A599
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Standard Of Care ◽  
Control Group ◽  
Cervical Lymph Nodes ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Long Acting

BackgroundRadiation (RT) and temozolomide (TMZ), which are standard of care for patients with glioblastoma (GBM), can cause prolonged severe lymphopenia. Lymphopenia, in turn, is an independent risk factor for shorter survival. Interleukin-7 (IL-7) is a cytokine that is required for T cell homeostasis and proliferation. IL-7 levels are inappropriately low in GBM patients with lymphopenia. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 rescues treatment-induced lymphopenia and improves survival.MethodsImmunocompetent C57BL/6 mice bearing two intracranial glioma models (GL261 and CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-I7 (10 mg/kg on the final day of RT completion). We profiled the CD3, CD8, CD4, FOXP3 cells in peripheral blood over time. We also immunoprofiled cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. Survival was monitored daily.ResultsMedian survival in mice treated with NT-I7 combined with RT was significantly longer than RT alone (GL261: 40d vs 34d, p<0.0021; CT2A: 90d vs 40d, p<0.0499) or NT-I7 alone (GL261: 40d vs 24d, p<0.008; CT2A: 90d vs 32d, p<0.0154). NT-I7 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261(40d vs 47d) and CT2A (90d vs 90d). Cytotoxic CD8+ T cells were increased in both peripheral blood (0.66 x 105 to 3.34 x 105; P≤0.0001) and tumor (0.53 x 103 to 1.83 x 103; P≤0.0001) in mice treated with NT-I7 when compared to control. Similarly, NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood (0.658 x 105 to 1.839 x 105 P≤0.0001) when compared to RT alone. There were decreases in tumor infiltrating FOXP3+ T-reg cells in mice treated with NT-I7 (1.9 x 104 to 0.75 x 104 P≤0.0001) and NT-I7 + RT (1.9 x 104 to 0.59 x 104 P≤0.0001) when compared to the control group without NT-I7. In addition, NT- I7 treatment increased CD8+ T cells in thymus, spleen, and lymph nodes.ConclusionsNT-I7 enhances cytotoxic CD8+ T lymphocytes systemically and in the tumor microenvironment, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).

Lack of the CD8+ cell anti-HIV factor in CD8+ cell granules

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 180-183 ◽  
Author(s):  
Carl E. Mackewicz ◽  
Baikun Wang ◽  
Sunil Metkar ◽  
Matthew Richey ◽  
Christopher J. Froelich ◽  
...  
Keyword(s):  
T Cells ◽  
Antiviral Activity ◽  
Cd8 T Cells ◽  
Culture Media ◽  
Cd4 Cells ◽  
Antiviral Protein ◽  
Cd8 Cells ◽  
Cd8 Cell ◽  
Anti Hiv ◽  
Primary Granule

Abstract In HIV infection, CD8+ cells show cytotoxic and noncytotoxic anti-HIV activity. The latter function is mediated, at least in part, by a secreted antiviral protein, the CD8+ cell antiviral factor (CAF). Because antiviral effector molecules, such as perforin and granzymes, reside in the exocytic granules of CD8+ T cells, we examined the possibility that granules contain CAF-like activity. CD8+ cells from HIV-infected individuals showing strong CAF-mediated antiviral activity were induced to release their granule constituents into culture media. Within 1 hour of stimulation, high levels of granzyme B (a primary granule constituent) were found in the culture fluids of previously activated CD8+ cells. The same culture fluids contained no or very low amounts of CAF activity, as measured with HIV-infected CD4+ cells. Maximal levels of CAF activity were not observed until 5 or 7 days after stimulation, consistent with typical CAF production kinetics. In addition, extracts of granules purified from antiviral CD8+ cells did not show any CAF activity, whereas the cytoplasmic fraction of these cells showed substantial levels of antiviral activity. These findings suggest that CAF does not reside at appreciable levels in the exocytic granules of antiviral CD8+ T cells. (Blood. 2003;102: 180-183)

scholarly journals CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

scholarly journals Age-related Defects in CD4 T Cell Cognate Helper Function Lead to Reductions in Humoral Responses

2004 ◽  
Vol 200 (12) ◽  
pp. 1613-1622 ◽  
Author(s):  
Sheri M. Eaton ◽  
Eve M. Burns ◽  
Kimberly Kusser ◽  
Troy D. Randall ◽  
Laura Haynes
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Donor Cell ◽  
The Elderly ◽  
Transfer Model ◽  
Age Related ◽  
Wide Range ◽  
Helper Function ◽  
Humoral Responses

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.

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