Age-associated up-regulation of a negative co-stimulatory receptor PD-1 in mouse CD4+ T cells

Shimada, Yukiko; Hayashi, Masami; Nagasaka, Yasuhiko; Ohno‐Iwashita, Yoshiko; Inomata, Mitsushi

doi:10.1016/j.exger.2009.05.003

Cited by 65 publications

(66 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The percentage of CD4 + T cells expressing PD-1 was increased in the spleen of aged C57Bl/6 mice (≥ 16-month old) compared to young mice (≤ 2-month old) as already described (Channappanavar et al 2009; Shimada et al 2009; Shimatani et al 2009), as well as in lymph nodes (LN) and lungs (Figure 1A and Table I). The same significant increase was observed when intracellular expression of PD-1 was measured in CD4 + T cells from the spleen (32.2 ± 7.2% in aged mice versus 7.5 ± 1.4% in young mice; p<0.05), the LN (11.2 ± 1.0% in aged mice versus 7.1 ± 0.6% in young mice; p=0.01), or the lung (19.2 ± 4.5% in aged mice versus 5.1 ± 0.3% in young mice; p=0.03).…”

Section: Resultssupporting

confidence: 80%

Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway

et al. 2010

View full text Add to dashboard Cite

SummaryProgrammed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to ageassociated T-cell dysfunction. Our data showed the following results in aged mice:

show abstract

Section: Resultssupporting

confidence: 80%

Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway

et al. 2010

View full text Add to dashboard Cite

show abstract

“…It has been proposed that impaired T‐cell function during aging is associated with an increase in the population of PD‐1‐expressing T cells (Channappanavar et al ., 2009; Shimada et al ., 2009; Lages et al ., 2010; Decman et al ., 2012). To address the relationship between the exhaustion of T cells and aging more specifically, we examined the expression of Tim‐3, which, along with PD‐1, defines T‐cell exhaustion during chronic infection or in tumors (Jin et al ., 2010; Sakuishi et al ., 2010) but has never been studied in a model of aging.…”

Section: Resultsmentioning

confidence: 99%

“…From the standpoint of T‐cell senescence and intrinsic alterations of T‐cell signaling, it is important to study the roles of inhibitory molecules in aged T cells (Fulop et al ., 2014). Recently, CD4 + and CD8 + T cells from aged mice have been shown to express several inhibitory receptor molecules, including PD‐1, LAG‐3, CTLA‐4, and KLRG1, all of which may be associated with defective T‐cell responses (Channappanavar et al ., 2009; Shimada et al ., 2009; Decman et al ., 2012). It has also been suggested that a PD‐1 blockade may partially restore T‐cell function (Lages et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1

et al. 2016

View full text Add to dashboard Cite

SummaryAging is accompanied by altered T‐cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD‐1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T‐cell exhaustion and aging‐associated immune dysfunction. In this study, we demonstrate that T‐cell immunoglobulin mucin domain‐3 (Tim‐3), another exhaustion marker, is up‐regulated on aged T cells, especially CD8+ T cells. Tim‐3‐expressing cells also produced PD‐1, but Tim‐3+ PD‐1+ CD8+ T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim‐3− PD‐1+ cells. Tim‐3+ PD‐1+ CD8+ T cells showed more evident properties associated with exhaustion than Tim‐3− PD‐1+ CD8+ T cells: an exhaustion‐related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL‐10 and induced normal CD8+ T cells to produce IL‐10, which might contribute to immune dysregulation in aged mice. The generation of Tim‐3‐expressing CD8+ T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vβ usage. In conclusion, we found that a CD8+ T‐cell population with age‐associated exhaustion was distinguishable by its expression of Tim‐3. These results provide clues for understanding the alterations that occur in T‐cell populations with age and for improving dysfunctions related to the aging of the immune system.

show abstract

“…Age-associated predominance of ICOS-expressing T-cells has been described in mice (Channappanavar et al 2009), yet to our knowledge, no data on its expression in aged human subjects exist. Results regarding the Treg marker Foxp3 and the inhibitory T-cell receptor CTLA-4 are somewhat controversial both in aged humans and mice (Channappanavar et al 2009;Hwang et al 2009;Leng et al 2002;Shimada et al 2009;Tsaknaridis et al 2003;Wakikawa et al 1997). Nevertheless, it must be noted that direct conclusions on the equality of immunosenescence in mice and humans are rather questionable and most importantly, examination of only a few molecules at a time does not give a comprehensive picture of ''net'' immunocompetence in vivo.…”

Section: Introductionmentioning

confidence: 91%

Expression profiling of immune-associated genes in peripheral blood mononuclear cells reveals baseline differences in co-stimulatory signalling between nonagenarians and younger controls: the vitality 90+ study

et al. 2010

View full text Add to dashboard Cite

The human immune system, especially the adaptive branch, substantially declines with ageing. Several distinct immunosenescent events have already been described, yet data regarding to age-associated baseline alterations in immune cell function is limited. Therefore, by using the TaqMan Human Immune Arrays we conducted a preliminary gene expression profiling of immune-related genes in the peripheral blood mononuclear cells of young individuals (aged 22–37 years, n = 13) and nonagenarians (n = 12), the latter being part of the Vitality 90+ Study. We also analysed the correlations between significantly regulated genes. The results revealed a significantly decreased expression of CCR7, CD19, CD28, CD40LG, ICOS, IL4, IL6 and LTA as well as significantly increased expression of FN1 in the nonagenarians as compared to the controls. Significant direct correlations were observed between the expression of CCR7 and CD19, CCR7 and ICOS, ICOS and CD19, ICOS and CD40LG, as well as CD40LG and CD28 in the nonagenarians but not in the controls. These results suggest that the key players of adaptive immunity i.e. the factors required for full lymphocyte activation are markedly and coordinately down-modulated in the very old individuals. Further research is, however, required to establish the relationship between these changes and the mechanisms of immunosenescence.

show abstract

Age-associated up-regulation of a negative co-stimulatory receptor PD-1 in mouse CD4+ T cells

Cited by 65 publications

References 21 publications

Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway

Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway

Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1

Expression profiling of immune-associated genes in peripheral blood mononuclear cells reveals baseline differences in co-stimulatory signalling between nonagenarians and younger controls: the vitality 90+ study

Contact Info

Product

Resources

About

Age-associated up-regulation of a negative co-stimulatory receptor PD-1 in mouse CD4+ T cells

Cited by 65 publications

References 21 publications

Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway

Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

Expression profiling of immune-associated genes in peripheral blood mononuclear cells reveals baseline differences in co-stimulatory signalling between nonagenarians and younger controls: the vitality 90+ study

Contact Info

Product

Resources

About

Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1