Immunosenescence: potential causes and strategies for reversal

2000 ◽  
Vol 28 (2) ◽  
pp. 250-254 ◽  
Author(s):  
R. Aspinall ◽  
D. Andrew
Keyword(s):  
T Cell ◽  
Immune Dysfunction ◽  
Careful Analysis ◽  
Experimental Therapy ◽  
Thymic Involution ◽  
Interleukin 7 ◽  
Cell Pool ◽  
Age Related ◽  
Peripheral T Cells ◽  
Laboratory Investigations

Age-related deterioration in immune function has been recognized in many species. In humans the clinical manifestation of such immune dysfunction is age-related increases in the susceptibility to certain infections and in the incidence of some autoimmune disease and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signalling function and in replicative ability following stimulus with antigen, mitogens or anti-CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the level of available interleukin 7. Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old cells with new output generated in the thymus. Problems to overcome in order for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

scholarly journals Interleukin-7 Regulates Bim Proapoptotic Activity in Peripheral T-Cell Survival

2009 ◽  
Vol 30 (3) ◽  
pp. 590-600 ◽  
Author(s):  
Wen Qing Li ◽  
Tad Guszczynski ◽  
Julie A. Hixon ◽  
Scott K. Durum
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Development ◽  
Cell Development ◽  
Effector Memory ◽  
Intracellular Location ◽  
Interleukin 7 ◽  
Peripheral T Cells ◽  
T Cell Survival

ABSTRACT Interleukin-7 (IL-7) is critical for T-cell development and peripheral T-cell homeostasis. The survival of pro-T cells and mature T cells requires IL-7. The survival function of IL-7 is accomplished partly through induction of the antiapoptotic protein Bcl-2 and inhibition of proapoptotic proteins Bax and Bad. We show here that the proapoptotic protein Bim, a BH3-only protein belonging to the Bcl-2 family, also plays a role in peripheral T-cell survival. Deletion of Bim partially protected an IL-7-dependent T-cell line and peripheral T cells, especially cells with an effector memory phenotype, from IL-7 deprivation. However, T-cell development in the thymus was not restored in IL-7−/− Rag2−/− mice reconstituted with Bim−/− bone marrow. IL-7 withdrawal altered neither the intracellular location of Bim, which was constitutively mitochondrial, nor its association with Bcl-2; however, a reduction in its association with the prosurvival protein Mcl-1 was observed. IL-7 withdrawal did not increase Bim mRNA or protein expression but did induce changes in the isoelectric point of BimEL and its reactivity with an antiphosphoserine antibody. Our findings suggest that the maintenance of peripheral T cells by IL-7 occurs partly through inhibition of Bim activity at the posttranslational level.

scholarly journals Thymic involution and rising disease incidence with age

2018 ◽  
Vol 115 (8) ◽  
pp. 1883-1888 ◽  
Author(s):  
Sam Palmer ◽  
Luca Albergante ◽  
Clare C. Blackburn ◽  
T. J. Newman
Keyword(s):  
T Cell ◽  
Power Law ◽  
Wide Spectrum ◽  
Disease Incidence ◽  
Thymic Involution ◽  
Incidence Data ◽  
Age Related ◽  
Exponential Decline ◽  
Combining Data ◽  
Cancer Types

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

scholarly journals The Role of the Thymus and Recent Thymic Migrants in the Maintenance of the Adult Peripheral Lymphocyte Pool

1998 ◽  
Vol 187 (11) ◽  
pp. 1839-1848 ◽  
Author(s):  
S.P. Berzins ◽  
R.L. Boyd ◽  
J.F.A.P. Miller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Export Ratio ◽  
Receptor Repertoire ◽  
Cell Pool ◽  
Peripheral T Cells ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire

The thymus is essential for the initial seeding of T cells to the periphery, but its role in maintaining the adult T cell pool remains poorly defined. We investigated whether changes to the rate of T cell export could form part of the mechanism(s) controlling the homeostatic regulation of the size and composition of the peripheral T cell pool. Using neonatal thymi grafted under the kidney capsule, we found that irrespective of whether the pool was oversupplied (by thymic grafts) or undersupplied (due to neonatal thymectomy), the thymic export rate was constant from both the host and graft thymus, and the periphery remained constant in size. Recent thymic emigrants (RTE) were also tracked to determine the extent of their acceptance into the T cell pool of a normal mouse. As a population, RTE are phenotypically mature, but were distinct from resident T cells in the periphery, being released in a CD4/CD8 ratio approximately twice that of established peripheral T cells. This export ratio is similar to that of T cells in the mature thymic compartment, but soon after entry into the periphery, the ratio falls, indicating separate thymic and peripheral regulation of the CD4/CD8 ratio. RTE may also be preferentially incorporated into the periphery, causing displacement of resident T cells, thus maintaining the size of the peripheral pool. Although not vital for the maintenance of a functional T cell pool, the acceptance of RTE in a “full” peripheral pool would ensure that the T cell receptor repertoire is kept diverse and that the T cell population encompasses a broad range of naive as well as memory T cells.

Neem leaf glycoprotein reverses tumor-induced and age-associated thymic involution to maintain peripheral CD8+ T cell pool

Immunotherapy ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 799-818
Author(s):  
Ipsita Guha ◽  
Avishek Bhuniya ◽  
Partha Nandi ◽  
Shayani Dasgupta ◽  
Anirban Sarkar ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Effector T Cells ◽  
Cell Maturation ◽  
Thymic Involution ◽  
Cell Pool ◽  
Tumor Reduction ◽  
T Cell Maturation

Aim: As tumor causes atrophy in the thymus to target effector-T cells, this study is aimed to decipher the efficacy of neem leaf glycoprotein (NLGP) in tumor- and age-associated thymic atrophy. Materials & methods: Different thymus parameters were studied using flow cytometry, reverse transcriptase PCR and immunocyto-/histochemistry in murine melanoma and sarcoma models. Results: Longitudinal NLGP therapy in tumor hosts show tumor-reduction along with significant normalization of thymic alterations. NLGP downregulates intrathymic IL-10, which eventually promotes Notch1 to rescue blockade in CD25+CD44+c-Kit+DN2 to CD25+CD44-c-Kit-DN3 transition in T cell maturation and suppress Ikaros/IRF8/Pu.1 to prevent DN2-T to DC differentiation in tumor hosts. The CD5intTCRαβhigh DP3 population was also increased to endorse CD8+ T cell generation. Conclusion: NLGP rescues tumor-induced altered thymic events to generate more effector T cells to restrain tumor.

Ontogeny, function, and peripheral homeostasis of regulatory T cells in the absence of interleukin-7

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2300-2306 ◽  
Author(s):  
Régis Peffault de Latour ◽  
Hélène C. Dujardin ◽  
Florence Mishellany ◽  
Odile Burlen-Defranoux ◽  
Julien Zuber ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
Bowel Disease ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Thymic Involution ◽  
Cell Compartment ◽  
Interleukin 7 ◽  
Inflammatory Bowel

Abstract Mice lacking interleukin-7 (IL-7–/– mice) have no signs of autoimmune disease, contrary to other models of lymphopenia. We investigated whether the absence of disease was due to the fact that IL-7 is dispensable for the ontogeny, function, and homeostasis of regulatory CD4+ T cells. We show here that the establishment of the peripheral pool of Foxp3-expressing regulatory cells is IL-7 independent, and the premature involution of the thymus in IL-7–/– mice does not change the representation of the CD4+CD25+ T-cell compartment. In addition, CD4+CD25+ T cells expand in the absence of IL-7, without losing Foxp3 expression. The frequency of activated peripheral CD4+ T cells increases with age in both the CD25– and CD25+ compartments, with the CD4+CD25+ T cells displaying signs of constant activation. IL-7–/– CD4+CD25+ T cells control inflammatory bowel disease induced by IL-7–/– T cells even in hosts lacking IL-7. Depletion of the CD25+ T-cell subset after thymic involution results in a mild form of inflammatory bowel disease (IBD), which resolves concomitantly with the regeneration of this subset. This study shows for the first time that IL-7–/– mice have a robust regulatory Foxp3-expressing CD4+ T-cell compartment that controls T-cell–mediated disease. It also highlights the potential of the regulatory Foxp3-expressing CD4+CD25– T-cell population to restore a functional CD4+CD25+ T-cell compartment through an IL-7–independent pathway.

scholarly journals Fate mapping reveals the age structure of the peripheral T cell compartment

2019 ◽  
Vol 116 (10) ◽  
pp. 3974-3981 ◽  
Author(s):  
Arnold Reynaldi ◽  
Norah L. Smith ◽  
Timothy E. Schlub ◽  
Cybelle Tabilas ◽  
Vanessa Venturi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Age Structure ◽  
Age Distribution ◽  
T Cell Response ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Cell Pool ◽  
Age Related ◽  
Rate Of Decay

Accumulating evidence indicates that the immune system does not develop in a linear fashion, but rather as distinct developmental layers formed from sequential waves of hematopoietic stem cells, each giving rise to unique populations of immune cells at different stages of development. Although recent studies have indicated that conventional CD8+T cells produced in early life persist into adulthood and exhibit distinct roles during infection, the developmental architecture of the peripheral T cell compartment remains undefined. In this study, we used a mouse model to permanently label CD8+T cells produced during distinct windows of development and traced their history to generate fate maps of CD8+T cells produced during different stages of life. We then used mathematical modeling to understand the age structure of the CD8+T cell compartment across the lifespan. Interestingly, we found that survival rate of CD8+T cells depends on both the age and developmental origin of the cells. Recently produced cells show an initial rapid decay rate, which slows with age of the animal at which the cells were produced. For cells produced at any age, the rate of decay also slows with the age of the cell. We derive a function to describe this and predict the “age distribution” of the CD8+T cell pool for animals of any given age. These data provide a quantitative framework for understanding the ontogeny of the CD8+T cell compartment and help to contextualize age-related changes in the CD8+T cell response to infection.

scholarly journals Obesity accelerates thymic aging

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3803-3812 ◽  
Author(s):  
Hyunwon Yang ◽  
Yun-Hee Youm ◽  
Bolormaa Vandanmagsar ◽  
Jennifer Rood ◽  
K. Ganesh Kumar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Surveillance ◽  
Cell Receptor ◽  
Effector Memory ◽  
Thymic Involution ◽  
Cell Repertoire ◽  
Diet Induced Obesity ◽  
Age Related ◽  
Repertoire Diversity

Abstract As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin−Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin−Sca1+CD117loCD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-β TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.

scholarly journals A peripheral CD4+ T cell precursor for naive, memory, and regulatory T cells

2010 ◽  
Vol 207 (13) ◽  
pp. 2883-2894 ◽  
Author(s):  
Chunfang Zhao ◽  
Joanna D. Davies
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Interleukin 7 ◽  
Cell Pool ◽  
Tcr Repertoire ◽  
B Cell Leukemia ◽  
Cd4 Cell

Mechanisms that control the size of the T cell pool, the ratio between naive cells and memory cells, the number and frequency of regulatory T cells, and T cell receptor (TCR) diversity are necessary to maintain immune integrity and avoid disease. We have previously shown that a subset of naive CD4+ T cells, defined by the expression on their surface of a very low density of CD44 (CD44v.low cells), can inhibit wasting and wasting-associated lymphopenia in mice with cancer. In this study, we further investigate the properties of CD44v.low cells and show that they are significantly more efficient than the remaining naive (CD44low or CD44int) and memory CD4+ cell subsets in reconstituting the overall size of the CD4+ T cell pool, creating a T cell pool with a diverse TCR repertoire, generating regulatory T cells that express forkhead box P3 (FoxP3), and promoting homeostatic equilibrium between naive, memory, and Foxp3+ regulatory T cell numbers. T cell population reconstitution by CD44v.low cells is thymus independent. Compared with CD44int cells, a higher percentage of CD44v.low cells express B cell leukemia/lymphoma 2, interleukin-7 receptor, and CD5. The data support a key role for CD4+ CD44v.low cells as peripheral precursors that maintain the integrity of the CD4+ T cell pool.

Cellular signalling pathways in immune aging and regeneration

2014 ◽  
Vol 42 (3) ◽  
pp. 651-656 ◽  
Author(s):  
Richard Aspinall ◽  
Antonio Lapenna ◽  
Christopher B-Lynch ◽  
Pierre O. Lang
Keyword(s):  
T Cell ◽  
Functional Decline ◽  
Fibroblast Cell ◽  
Cell Receptor ◽  
Interleukin 7 ◽  
Human Cd34 ◽  
Cell Pool ◽  
Cd34 Cells ◽  
Different Sources ◽  
Fibroblast Cell Lines

The thymus is one of the cornerstones of an effective immune system. It produces new T-cells for the naïve T-cell pool, thus refreshing the peripheral repertoire. As we age, the thymus atrophies and there is a decrease in the area of active T-cell production. A decline in the output of the thymus eventually leads to changes in the peripheral T-cell pool which includes increases in the number of cells at or near their replicative limit and contraction of the repertoire. Debate about the age-associated changes in the thymus leading to functional decline centres on whether this is due to problems with the environment provided by the thymus or with defects in the progenitor cell compartment. In mice, the evidence points towards problems in the epithelial component of the thymus and the production of IL-7 (interleukin 7). But there are discussions about how appropriate mouse models are for human aging. We have developed a simple system that utilizes both human keratinocyte and fibroblast cell lines arrayed on a synthetic tantalum-coated matrix to provide a permissive environment for the maturation of human CD34+ haemopoietic progenitor cells into mature CD4+ or CD8+ T-lymphocytes. We have characterized the requirements for differentiation within these cultures and used this system to compare the ability of CD34+ cells derived from different sources to produce mature thymocytes. The TREC (T-cell receptor excision circle) assay was used as a means of identifying newly produced thymocytes.

scholarly journals Prevention of age-related T cell apoptosis defect in CD2-fas-transgenic mice.

1995 ◽  
Vol 182 (1) ◽  
pp. 129-137 ◽  
Author(s):  
T Zhou ◽  
C K Edwards ◽  
J D Mountz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cell Function ◽  
Thymic Involution ◽  
Age Related ◽  
Induced Apoptosis ◽  
And Function ◽  
Old Mice ◽  
Young Mice

T cell dysfunction and thymic involution are major immunologic abnormalities associated with aging. Fas (CD95) is a bifunctional molecule that is critical for apoptosis and stimulation during T cell development, but the role of Fas during aging has not been determined. Fas expression and function on T cells from old (22-26-mo-old) mice was compared with young (2-mo-old) mice and old CD2-fas-transgenic mice. Fas expression and ligand-induced apoptosis were decreased on T cells from old mice compared with young mice. This correlated with an age-related increase in CD44+Fas- T cells. There was a marked decrease in the proliferation of T cells from old mice after anti-CD3 stimulation compared with young mice. Anti-CD3-stimulated T cells from young mice exhibited increased production of interleukin (IL)-2 and decreased production of interferon-gamma and IL-10 compared with old mice. There was an age-related decrease in the total thymocyte count from 127 +/- 10 cells in young mice compared with 26 +/- 8 x 10(6) in old mice. In 26-mo-old CD2-fas-transgenic mice, Fas and CD44 expression, Fas-induced apoptosis, T cell proliferation, and cytokine production were comparable to that of the young mice. These results suggest that T cell senescence with age is associated with defective apoptosis, and that the CD2-fas transgene allows maintenance of Fas apoptosis function and T cell function in aged mice comparable to that of young mice.

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