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Homeostatic Proliferation (homeostatic + proliferation)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010
Yufei Wang
Abstract Evidence is presented that thermal or oxidizing stress-activated DC interact with CD4+ T cells to induce and maintain a TCR-independent homeostatic memory circuit. Stress-activated DC expressed endogenous intra-cellular and cell surface HSP70. The NF-,B signalling pathway was activated and led to the expression of membrane-associated IL-15 molecules. These interacted with the IL-15 receptor complex on CD4+ T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-, production. CD40 ligand on CD4+ T cells in turn re-activated CD40 molecules on DC, inducing DC maturation and IL-15 expression thereby maintaining the feedback circuit. The proliferating CD4+ T cells were characterized as CD45RA, CD62L+ central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC-class-II-TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC-class II antibodies. These findings suggest that stress can activate a DC-CD4+ T-cell interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory. [source]

Expression and function of the adaptor protein Gads in murine B,cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2005
Thomas
Abstract Nearly all hematopoietic receptors are dependent on adaptor proteins for the activation of downstream signaling pathways. The Gads adaptor protein is expressed in many hematopoietic tissues, including bone marrow, lymph node, and spleen. Using intracellular staining, we detected Gads protein in a number cells, including B,cells, T,cells, NK cells, monocytes, and plasmacytoid DC, but not in macrophages, neutrophils, or monocyte-derived DC. In the B,cell compartment, Gads was first expressed after immature B,cells leave the bone marrow and was down-regulated after B,cell antigen receptor (BCR) ligation. Female Gads,/, mice had increased numbers of splenic B,cells, as compared to female Gads+/+ mice, suggesting a role for Gads in B,cell homeostasis. Although B,cell production and turnover of splenic B,cell subsets appeared normal in Gads,/, mice, homeostatic proliferation was significantly impaired in Gads,/, B,cells. Whereas BCR ligation can induce apoptosis in wild-type transitional stage 1 (T1) B,cells, Gads,/, T1 B,cells were resistant to BCR-induced apoptosis. Gads,/, B,cells also showed increased BCR-mediated calcium mobilization. We conclude that Gads may have a negative regulatory role in signaling through survival pathways, and is necessary for normal homeostatic proliferation in B,cells. [source]

Defective T-cell function leading to reduced antibody production in a kleisin-, mutant mouse

IMMUNOLOGY, Issue 2 2008
Katharine M. Gosling
Summary The recently described nessy (Ncaph2nes/nes) mutant mouse strain has a defect in T-cell development caused by a mutation in the ubiquitous kleisin-, (also known as Ncaph2). Kleisin- , is a subunit of the condensin II complex involved in chromosome condensation during mitosis. The nessy phenotype is characterized by CD44hi CD8+ peripheral T cells, 10,20% of normal thymocyte numbers and 2·5-fold fewer ,, T cells in the spleen compared with wild-type mice. In this study we examined the effect of the nessy mutation in kleisin-, on the immune response by challenging mice with an attenuated strain of Salmonella. Results showed that nessy mice control bacterial load as effectively as wild-type mice but exhibit a reduced antibody titre. Further experiments revealed that while the T-dependent antibody response was diminished in nessy mice the T-independent response was normal, suggesting that the defect was the result of T-cell function and not B-cell function. In vitro activation assays showed that nessy T cells have a lower capacity to up-regulate the early activation marker CD69 than wild-type T cells. Upon transfer into RAG,/, mice, nessy and wild-type CD4 T cells showed equivalent homeostatic proliferation, while nessy CD8 T cells proliferated more than their wild-type counterparts. When cultured with anti-T-cell receptor , or concanavalin A, nessy T cells were found to die faster than wild-type T cells. These data indicate that kleisin-, is required for a normal immune response, and represent the first demonstration of a role for kleisin-, in T-cell function. [source]

Exogenous IL-15 in Combination With IL-15R, Rescues Natural Killer Cells From Apoptosis Induced by Chronic Alcohol Consumption

ALCOHOLISM, Issue 3 2009
Hui Zhang
Background:, Chronic alcohol consumption reduces the percentage and number of peripheral natural killer (NK) cells in mice and in humans. The underlying mechanism for these changes is only partly known. We recently found that chronic alcohol consumption inhibits NK cell release from the bone marrow (BM) and that this is associated with a decrease in splenic NK cells. The number of peripheral NK cells is tightly controlled by homeostatic proliferation. It is not known whether this mechanism is initiated in response to the reduction in splenic NK cells, or if so, why the steady state levels of NK cells are not restored. Methods:, To examine this mechanism, female C57BL/6 mice were given 20% w/v alcohol in the drinking water for 3 months. NK cell proliferation and apoptosis were determined before and after treatment with IL-15 alone or combined with its alpha receptor. Results:, Chronic alcohol consumption invoked homeostatic proliferation of splenic NK cells in an attempt to return NK cells to normal levels; however, this did not happen due to enhanced apoptosis of NK cells relative to proliferation. Chronic alcohol consumption decreased IL-15 producing cells in the spleen but not in the BM. The numbers of NK cells in the alcohol-consuming mice returned to normal levels in the spleen and were higher than normal in the BM after 2 daily injections of IL-15; however, the enhanced rate of apoptosis due to alcohol consumption was not decreased in the spleen or BM. Combined IL-15 and IL-15R, treatment decreased apoptosis of NK cells from alcohol-consuming mice to levels similar to untreated water-drinking mice and greatly increased the percentage and number of NK cells in both the spleen and BM. Conclusion:, Chronic alcohol consumption causes a self-unrecoverable loss of NK cells in the spleen by compromising NK cell release from the BM and enhancing splenic NK cell apoptosis that can be reversed with IL-15/IL-15R, treatment. [source]

Memory T-Cell Predominance Following T-Cell Depletional Therapy Derives from Homeostatic Expansion of Naive T Cells

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009
A. Sener
T-cell depletion reportedly leads to alterations in the T-cell compartment with predominant survival of memory phenotype CD4 T cells. Here, we asked whether the prevalence of memory T cells postdepletion results from their inherent resistance to depletion and/or to the homeostatic expansion of naive T cells and their phenotypic conversion to memory, which is known to occur in lymphopenic conditions. Using a ,mosaic memory' mouse model with trackable populations of alloreactive memory T cells, we found that treatment with murine antithymocyte globulin (mATG) or antilymphocyte serum (ALS) effectively depleted alloreactive memory CD4 T cells, followed by rapid homeostatic proliferation of endogenous CD4 T cells peaking at 4 days postdepletion, with no homeostatic advantage to the antigen-specific memory population. Interestingly, naive (CD44lo) CD4 T cells exhibited the greatest increase in homeostatic proliferation following mATG treatment, divided more extensively compared to memory (CD44hi) CD4 T cells and converted to a memory phenotype. Our results provide novel evidence that memory CD4 T cells are susceptible to lymphodepletion and that the postdepletional T-cell compartment is repopulated to a significant extent by homeostatically expanded naive T cells in a mouse model, with important important implications for immune alterations triggered by induction therapy. [source]

CD4+CD25+FOXP3+ Regulatory T Cells Increase De Novo in Kidney Transplant Patients After Immunodepletion with Campath-1H

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2008
D. D. Bloom
Campath-1H (Alemtuzumab) is an effective immunodepletion agent used in renal transplantation. To evaluate its influence on T lymphocytes during repletion, we analyzed peripheral blood from Campath-1H-treated renal allograft recipients for the presence of FOXP3+ regulatory T (Treg) cells. Flow cytometry demonstrated that CD4+CD25+FOXP3+ lymphocytes increased significantly within the CD4+ T-cell population, skewing Treg/Teff (T effector) ratios for up to several years. In contrast, Treg levels in patients treated with anti-CD25 (Basiliximab) and maintained on CsA demonstrated a sustained decrease. The increase in Tregs in Campath-1H treated patients developed independent of maintenance immunosuppression. Importantly, the increase in Tregs was not fully explained by their homeostatic proliferation, increased thymic output, or Treg sparing, suggesting de novo generation/expansion. Consistent with this, in vitro stimulation of PBMCs with Campath-1H, with or without anti-CD3, activation led to an increase in CD4+CD25+FOXP3+ cells that had suppressive capabilities. Together, these data suggest that Campath-1H promotes an increase in peripheral Tregs and may act as an intrinsic generator of Tregs in vivo. [source]

Premature aging of the immune system in children with juvenile idiopathic arthritis

ARTHRITIS & RHEUMATISM, Issue 7 2008
Martina Prelog
Objective Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence. Methods To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation. Results JIA patients showed an accelerated loss of CD4+,CD45RA+,CD62L+ naive T cells with advancing age and a compensatory increase in the number of CD4+,CD45RO+ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4+,CD45RA+ naive T cells compared with age-matched healthy donors (P = 0.002). TREC numbers correlated with age only in healthy donors (P = 0.0001). Telomeric erosion in CD4+,CD45RA+ naive T cells was increased in JIA patients (P = 0.01). The percentages of Ki-67,positive CD4+,CD45RA+ naive T cells were increased in JIA patients (P = 0.001) and correlated with disease duration (P = 0.003), which was also an independent factor contributing to telomeric erosion (P = 0.04). Conclusion Our findings suggest that age-inappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies. [source]