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.

Clinical stem-cell sources contain CD8+CD3+ T-cell receptor–negative cells that facilitate bone marrow repopulation with hematopoietic stem cells

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1735-1738 ◽  
Author(s):  
Stephanie Bridenbaugh ◽  
Linda Kenins ◽  
Emilie Bouliong-Pillai ◽  
Christian P. Kalberer ◽  
Elena Shklovskaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Cd8 Cells ◽  
Human Cd34 ◽  
Cd34 Cells

Abstract Clinical observations in patients undergoing bone marrow transplantation implicate the involvement of CD8+ cells in promoting the stem-cell engraftment process. These findings are supported by mouse transplant studies, which attributed the engraftment-facilitating function to subpopulations of murine CD8+ cells, but the analogous cells in humans have not been identified. Here, we report that clinical stem-cell grafts contain a population of CD8α+CD3ϵ+ T-cell receptor– negative cells with an engraftment facilitating function, named candidate facilitating cells (cFCs). Purified cFC augmented human hematopoiesis in NOD/SCID mice receiving suboptimal doses of human CD34+ cells. In vitro, cFCs cocultured with CD34+ cells increased hematopoietic colony formation, suggesting a direct effect on clonogenic precursors. These results provide evidence for the existence of rare human CD8+CD3+TCR− cells with engraftment facilitating properties, the adoptive transfer of which could improve the therapeutic outcome of stem-cell transplantation.

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.

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.

Effects of exogenous interleukin-7 on human thymus function

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2851-2858 ◽  
Author(s):  
Yukari Okamoto ◽  
Daniel C. Douek ◽  
Richard D. McFarland ◽  
Richard A. Koup
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Receptor ◽  
Cellular Division ◽  
Hematopoietic Stem ◽  
Human Thymus ◽  
Interleukin 7

Abstract Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a+CD3−CD4+CD8+stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3− cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-αβ rearrangement and indicate the potential use of IL-7 for enhancing de novo naı̈ve T-cell generation in immunocompromised patients.

scholarly journals Interleukin-7 Enhances Proliferation Responses to T-Cell Receptor Stimulation in Naïve CD4+ T Cells from Human Immunodeficiency Virus-Infected Persons

2007 ◽  
Vol 81 (22) ◽  
pp. 12670-12674 ◽  
Author(s):  
Douglas A. Bazdar ◽  
Scott F. Sieg
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Healthy Controls ◽  
Receptor Stimulation ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Antigen Presenting

ABSTRACT Proliferation responses of naïve CD4+ T cells to T-cell receptor and interleukin-7 (IL-7) stimulation were evaluated by using cells from human immunodeficiency virus-positive (HIV+) donors. IL-7 enhanced responses to T-cell receptor stimulation, and the magnitude of this enhancement was similar in cells from healthy controls and from HIV+ subjects. The overall response to T-cell receptor stimulation alone or in combination with IL-7, however, was diminished among viremic HIV+ donors and occurred independent of antigen-presenting cells. Frequencies of CD127+ cells were related to the magnitudes of proliferation enhancement that were mediated by IL-7. Thus, IL-7 enhances but does not fully restore the function of naïve CD4+ T cells from HIV-infected persons.

scholarly journals Interleukin 7 Receptor Control of  T Cell Receptor γ Gene Rearrangement: Role of Receptor-associated Chains and Locus Accessibility

1998 ◽  
Vol 188 (12) ◽  
pp. 2233-2241 ◽  
Author(s):  
Scott K. Durum ◽  
Serge Candèias ◽  
Hiroshi Nakajima ◽  
Warren J. Leonard ◽  
Allison M. Baird ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
T Cell Receptor ◽  
Dna Cleavage ◽  
Gene Rearrangement ◽  
Trichostatin A ◽  
Cell Receptor ◽  
Lymphoid Cells ◽  
Janus Kinase ◽  
Interleukin 7

VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R)α−/− murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-γ locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7Rα to rearrangement of the TCR-γ locus requires the γc receptor chain and the γc-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-γ locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7Rα−/− thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7Rα−/− thymocytes. Instead, the TCR-γ locus was shown to be methylated in IL-7Rα−/− thymocytes. Treatment of IL-7Rα−/− precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-γ gene rearrangement. This data supports the model that IL-7R promotes TCR-γ gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.

scholarly journals Priming of T cells to Fas-mediated proliferative signals by interleukin-7

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1195-1204 ◽  
Author(s):  
Bence Rethi ◽  
Nancy Vivar ◽  
Stefano Sammicheli ◽  
Caroline Fluur ◽  
Nicolas Ruffin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cell Receptor ◽  
Cell Depletion ◽  
Activated T Cells ◽  
T Cell Depletion ◽  
Interleukin 7 ◽  
Costimulatory Signals ◽  
Opposing Effects

Abstract T-cell depletion associated with HIV infection or cytoreductive therapies triggers potential T-cell regenerative mechanisms such as peripheral T-lymphocyte expansion to weak antigenic stimuli and the increased availability of interleukin-7 (IL-7), a cytokine with potent antiapoptotic and proliferative activities. Deleterious mechanisms also associated with lymphopenia, such as increased Fas expression and apoptosis of T cell, however, may result in opposing effects. In this study, we show that Fas molecules, primarily associated with T-cell depletion in lymphopenic settings, may also contribute to compensatory T-cell expansion through transmitting costimulatory signals to suboptimally activated T cells. Proliferation of T lymphocytes in response to concomitant Fas and T-cell receptor (TCR) triggering was shown to be increased in HIV-infected individuals compared with noninfected controls. As IL-7 levels are often elevated in lymphopenic individuals in association with increased Fas expression, we analyzed whether IL-7 would influence Fas-mediated proliferative signals in T cells. We show that IL-7 is able to increase the efficacy of Fas to induce proliferation of suboptimally activated T cells. Thus, high IL-7 levels associated with lymphopenic conditions may simultaneously induce sensitivity to Fas-mediated apoptosis in nonactivated T cells and increase Fas-induced costimulatory signals in T cells recognizing low-affinity antigens.

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