Activation Defects in T Cells From Old Mice

2020 ◽  
pp. 55-63
Author(s):  
Richard A. Miller ◽  
Adam Lerner ◽  
Ben Philosophe ◽  
John Macauley
Keyword(s):  
T Cells ◽  
Old Mice

scholarly journals Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

2021 ◽  
Vol 7 (21) ◽  
pp. eabe4601
Author(s):  
Sandro Da Mesquita ◽  
Jasmin Herz ◽  
Morgan Wall ◽  
Taitea Dykstra ◽  
Kalil Alves de Lima ◽  
...  
Keyword(s):  
T Cells ◽  
Cognitive Decline ◽  
Brain Aging ◽  
Therapeutic Potential ◽  
T Cell Response ◽  
Age Related ◽  
Lymphatic Vasculature ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

Expression of a proto-oncogene (proto-myb) in hemopoietic tissues of mice

1984 ◽  
Vol 4 (7) ◽  
pp. 1206-1212
Author(s):  
D Sheiness ◽  
M Gardinier
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Lymph Nodes ◽  
Blot Hybridization ◽  
Protein Product ◽  
T Cell Differentiation ◽  
Dot Blot ◽  
Cellular Homolog ◽  
Old Mice ◽  
Transforming Gene

This study addressed the possibility that proto-myb (also called c-myb), the cellular homolog of a retroviral transforming gene, plays a role in hemopoiesis, particularly during maturation of T cells. By gel blot hybridization, we confirmed previous reports that proto-myb transcripts are found at much higher levels in thymic lymphocytes and cells of the erythroid lineage than in other tissue sources. Using dot blot hybridizations, we demonstrated further that similar levels of proto-myb expression are found in thymic lymphocytes taken from young mice with active thymuses and from old mice whose thymuses have undergone involution and that the extent of proto-myb expression decreases at least 10-fold as T cells progress from immature cortical thymocytes to the mature, resting T cells taken from lymph nodes. These results suggest that the protein product of proto-myb functions during T-cell differentiation.

scholarly journals Impairment in a negative regulatory system for TCR signaling in CD4+T cells from old mice

FEBS Letters ◽  
2007 ◽  
Vol 581 (16) ◽  
pp. 3039-3043 ◽  
Author(s):  
Mitsushi Inomata ◽  
Yukiko Shimada ◽  
Masami Hayashi ◽  
Jun Shimizu ◽  
Yoshiko Ohno-Iwashita
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Regulatory System ◽  
Tcr Signaling ◽  
Old Mice

scholarly journals Interleukin-12 is sufficient to promote antigen-independent interferon-γ production by CD8 T cells in old mice

Immunology ◽  
2009 ◽  
Vol 128 (1pt2) ◽  
pp. e679-e690 ◽  
Author(s):  
Erin K. Rottinghaus ◽  
Bridget Vesosky ◽  
Joanne Turner
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Old Mice

scholarly journals Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Neha R Deshpande ◽  
Heather L Parrish ◽  
Michael S Kuhns
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Biology ◽  
Fold Increase ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Fundamental Aspect ◽  
Cell Compartment ◽  
Old Mice

T-cell recognition of self and foreign peptide antigens presented in major histocompatibility complex molecules (pMHC) is essential for life-long immunity. How the ability of the CD4+ T-cell compartment to bind self- and foreign-pMHC changes over the lifespan remains a fundamental aspect of T-cell biology that is largely unexplored. We report that, while old mice (18–22 months) contain fewer CD4+ T-cells compared with adults (8–12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. Old mice also have more cells that bind individual or multiple distinct foreign-pMHCs, and the fold increase in pMHC-binding populations is directly related to their CD5 levels. These data demonstrate that the CD4+ T-cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T-cell receptor interactions with self-pMHC.

scholarly journals Quantitative Restoration of Immune Defense in Old Animals Determined by Naive Antigen-Specific CD8 T cell Numbers

2021 ◽  
Author(s):  
Jennifer Uhrlaub ◽  
Mladen Jergović ◽  
Christine M. Bradshaw ◽  
Sandip Sonar ◽  
Christoper P. Coplen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Neutralizing Antibody ◽  
Immune Defense ◽  
Cell Numbers ◽  
Specific Effector ◽  
The Face ◽  
Old Mice

Many older humans and animals exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naive T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of WNV in both humans naturally exposed to, and mice experimentally infected with, West Nile virus (WNV). To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (>four-fold) and NS4b:H-2Db-restricted antigen-specific CD8 T cells (two-fold). This improved the numbers of NS4b-specific CD8 T cells detected at the peak of the response against WNV, but not survival in the face of WNV challenge. IL-7C treated old animals also showed no improvement in WNV-specific effector immunity (neutralizing antibody and in vivo T cell cytotoxicity). To test quantitative limits to which CD8 Tn cell restoration could improve protective immunity, we transferred graded doses of Ag-specific precursors into old mice, and showed that injection of 5,400 (but not of 1,800 or 600) adult naive WNV-specific CD8 T cells significantly increased survival after WNV. These results set quantitative limits to the level of Tn reconstitution necessary to improve immune defense in older organisms, and are discussed in light of targets of immune reconstitution.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between children and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown.Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA.Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group.Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Single-cell sequencing reveals antitumor characteristics of intratumoral immune cells in old mice

2021 ◽  
Vol 9 (10) ◽  
pp. e002809
Author(s):  
Cangang Zhang ◽  
Lei Lei ◽  
Xiaofeng Yang ◽  
Kaili Ma ◽  
Huiqiang Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Single Cell ◽  
Immune Cells ◽  
Tumor Development ◽  
Cell Receptor ◽  
Sequencing Analysis ◽  
Tcr Diversity ◽  
Old Mice ◽  
Young Mice

BackgroundAging has long been thought to be a major risk factor for various types of cancers. However, accumulating evidence indicates increased resistance of old animals to tumor growth. An in-depth understanding of how old individuals defend against tumor invasion requires further investigations.MethodsWe revealed age-associated alterations in tumor-infiltrating immune cells between young and old mice using single-cell RNA and coupled T cell receptor (TCR) sequencing analysis. Multiple bioinformatics methods were adopted to analyze the characteristics of the transcriptome between two groups. To explore the impacts of young and old CD8+ T cells on tumor growth, mice were treated with anti-CD8 antibody every 3 days starting 7 days after tumor inoculation. Flow cytometry was used to validate the differences indicated by sequencing analysis between young and old mice.ResultsWe found a higher proportion of cytotoxic CD8+ T cells, naturally occurring Tregs, conventional dendritic cell (DC), and M1-like macrophages in tumors of old mice compared with a higher percentage of exhausted CD8+ T cells, induced Tregs, plasmacytoid DC, and M2-like macrophages in young mice. Importantly, TCR diversity analysis showed that top 10 TCR clones consisted primarily of exhausted CD8+ T cells in young mice whereas top clones were predominantly cytotoxic CD8+ T cells in old mice. Old mice had more CD8+ T cells with a ‘progenitor’ and less ‘terminally’ exhausted phenotypes than young mice. Consistently, trajectory inference demonstrated that CD8+ T cells preferentially differentiated into cytotoxic cells in old mice in contrast to exhausted cells in young mice. Importantly, elimination of CD8+ T cells in old mice during tumor growth significantly accelerated tumor development. Moreover, senescent features were demonstrated in exhausted but not cytotoxic CD8+ T cells regardless of young and old mice.ConclusionsOur data revealed that a significantly higher proportion of effector immune cells in old mice defends against tumor progression, providing insights into understanding the altered kinetics of cancer development and the differential response to immunotherapeutic modulation in elderly patients.

Sign in / Sign up

Export Citation Format

Share Document