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

Lages, Celine S.; Lewkowich, Ian P.; Sproles, Alyssa; Wills‐Karp, Marsha; Chougnet, Claire

doi:10.1111/j.1474-9726.2010.00611.x

Cited by 113 publications

(119 citation statements)

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“…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%

“…Consistent with the previous study, most Tim‐3 − PD‐1 + cells are of the memory phenotype (CD44 hi ) and that a large numbers of these cells are EM cells (Fig. 2A,B) (Lages et al ., 2010). In contrast, Tim‐3 + PD‐1 + CD8 + T cells are mostly CD62L lo T cells, and the expression levels of CD44 in these cells are mainly distributed from intermediate to low, which characterizes them as revertant phenotype cells (Figs 2A,B, and S2) (Akbar & Fletcher, 2005; Lages et al ., 2010).…”

Section: Resultsmentioning

confidence: 99%

“…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). Thus, understanding the increased T‐cell inhibitory signaling that occurs with aging is an important step toward developing approaches to rescue T‐cell senescence.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…T cells become exhausted with age, losing functionality for unclear reasons that could include long‐term antigenic stimulation or chronic inflammation (Lages et al ., 2010). PD‐1 is an exhausted T‐cell marker (Barber et al ., 2006).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, long‐term eRapa reduced phenotypically exhausted T cells that can be functionally impaired and contribute to age‐related immune dysfunction (Lages et al ., 2010). Gene array data showed that PD‐1 + cells in eRapa‐treated mice had reduced signature exhaustion gene expression suggesting better function versus PD‐1 + control T cells.…”

Section: Discussionmentioning

confidence: 99%

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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SummaryThe mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.

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Aging and immunotherapies: New horizons for the golden ages

Hamilton

Henry

2020

Aging and Cancer

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The life expectancy of the world's elderly population (65 and older) continues to reach new milestones with older individuals currently comprising greater than 8.5% (617 million) of the world's population. This percentage is predicted to approach 20% of the world's population by 2050 (representing 1.6 billion people). Despite this amazing feat, many healthcare systems are not equipped to handle the multitude of diseases that commonly manifest with age, including most types of cancers. As the world's aging population grows, cancer treatments continue to evolve. Immunotherapies are a new drug class that has revolutionized our ability to treat previously intractable cancers; however, their efficacy in patients with compromised immune systems remains unclear. In this review, we will discuss how aging-associated losses in immune homeostasis impact the efficacy and safety of immunotherapy treatment in preclinical models of aging. We will also discuss how these findings translate to elderly patients receiving immunotherapy treatment for refractory and relapsed cancers, as well as, strategies that could be explored to improve the efficacy of immunotherapies in aged patients.

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

Cited by 113 publications

References 57 publications

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

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

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Aging and immunotherapies: New horizons for the golden ages

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

Cited by 113 publications

References 57 publications

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

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

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Aging and immunotherapies: New horizons for the golden ages

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

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