Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly
. To define the contribution of immune system ageing to organism ageing, here we ...selectively deleted Ercc1, which encodes a crucial DNA repair protein
, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence
in the immune system only. We show that Vav-iCre
;Ercc1
mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice
. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre
;Ercc1
or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre
;Ercc1
mice with rapamycin reduced markers of senescence in immune cells and improved immune function
. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
With aging, there is increased dysfunction of both innate and adaptive immune responses, which contributes to impaired immune responses to pathogens and greater mortality and morbidity. This ...age-related immune dysfunction is defined in general as immunosenescence and includes an increase in the number of memory T cells, loss of ability to respond to antigen and a lingering level of low-grade inflammation. However, certain features of immunosenescence are similar to cellular senescence, which is defined as the irreversible loss of proliferation in response to damage and stress. Importantly, senescence cells can develop an inflammatory senescence-associated secretory phenotype (SASP), that also drives non-autonomous cellular senescence and immune dysfunction. Interestingly, viral infection can increase the extent of immune senescence both directly and indirectly, leading to increased immune dysfunction and inflammation, especially in the elderly. This review focuses on age-related immune dysfunction, cellular senescence and the impaired immune response to pathogens.
Aging is associated with the highest risk for morbidity and mortality to chronic or metabolic diseases, which are present in 50% of the elderly. Improving metabolic and immune function of the elderly ...would improve quality of life and reduce the risk for all other diseases. Tissue-resident macrophages and the NLRP3 inflammasome are established drivers of inflammaging and metabolic dysfunction. Energy-sensing signaling pathways connect sterile and metabolic inflammation with cellular senescence and tissue dysfunction. We discuss recent advances in the immunometabolism field. Common themes revealed by recent publications include the alterations in metabolic signaling (SIRTUIN, AMPK, or mTOR pathways) in aged immune cells, the impact of senescence on inflammaging and tissue dysfunction, and the age-related changes in metabolic tissues, especially adipose tissue, as an immunological organ. Promising gerotherapeutics are candidates to broadly target nutrient and energy sensing, inflammatory and senescence pathways, and have potential to improve healthspan and treat age-related diseases.
Summary
Aging 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.
Wnt/β‐catenin signaling plays a crucial role during embryogenesis and tumorigenesis, and in T cells, promotes the differentiation of Th2 cells. However, the role of Wnt signals in the differentiation ...and maintenance of human Th17 cells remains poorly understood. We found that the higher levels of IL‐17 in the synovial fluid of rheumatoid arthritis (RA) patients compared with that of osteoarthritis (OA) patients were associated with a higher concentration of sFRP1 (secreted Frizzled‐Related Protein 1), an inhibitor of the Wnt/β‐catenin pathway. The addition of sFRP1 during TCR‐mediated stimulation induced a significant increase in IL‐17 production by both naïve and memory CD4+ T cells. Moreover, under Th17‐differentiation conditions, the addition of sFRP1 significantly reduced the requirement for TGF‐β. Mechanistically, we observed that sFRP1 significantly enhanced the phosphorylation of Smad2/3 in CD4+ T cells upon TGF‐β stimulation and that blocking TGF‐β signaling abolished the Th17‐promoting activity of sFRP1. Our findings reveal a novel function for sFRP1 as a potent inducer of human Th17‐cell differentiation. Consequently, sFRP1 may represent a promising target for the treatment of Th17‐mediated disease in humans.
Retinoic acid (RA) is a diverse regulator of immune responses. Although RA promotes natural killer T (NKT) cell activation in vitro by increasing CD1d expression on antigen‐presenting cells (APCs), ...the direct effects of RA on NKT‐cell responses in vivo are not known. In the present study, we demonstrated the effect of RA on the severity of Con A‐induced hepatitis and molecular changes of NKT cells. First, we demonstrated that Con A‐induced liver damage was ameliorated by RA. In correlation with cytokine levels in serum, RA regulated the production of IFN‐γ and IL‐4 but not TNF‐α by NKT cells without influencing the NKT‐cell activation status. However, RA did not alleviate α‐GalCer‐induced liver injury, even though it reduced IFN‐γ and IL‐4 but not TNF‐α levels in serum. This regulation was also detected when liver mononuclear cells (MNCs) or NKT hybridoma cells were treated with RA in vitro. The regulatory effect of RA on NKT cells was mediated by RAR‐α, and RA reduced the phosphorylation of MAPK. These results suggest that RA differentially modulates the production of effector cytokines by NKT cells in hepatitis, and the suppressive effect of RA on hepatitis varies with the pathogenic mechanism of liver injury.
Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune ...escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly understood. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway. Osteopontin-mediated extramedullary myelopoiesis was directly associated with increased MDSCs in tumor-bearing hosts. More importantly, osteopontin silencing in tumor cells delayed both tumor growth and extramedullary myelopoiesis, while the same treatment did not affect tumor growth in vitro. Finally, treatment with an antibody against osteopontin inhibited tumor growth and synergized with cell-based immunotherapeutic vaccines in mediating antitumor immunity. Our findings unveil a novel immunosuppressive role for tumor-derived osteopontin and offer a rationale for its therapeutic targeting in cancer treatment.
Myeloid-derived suppressor cells (MDSCs), which are known to be accumulated in the blood, spleen, and bone marrow of tumor-bearing mice and cancer patients, were tested as APCs for a cellular vaccine ...because they have phenotypical similarity with inflammatory monocytes and may be differentiated from the same precursors as monocytes. Although MDSCs have immunosuppressive properties, in vivo transferred MDSCs, which present tumor Ag and NKT cell ligand (alpha-galactosylceramide), significantly prolonged survival time in metastatic tumor-bearing mice in a CD8(+) cell-, NK cell-, and NKT cell-dependent manner vs a CD4(+) T cell- and host dendritic cell-independent manner. Major concerns about using MDSCs as APCs in a vaccine are their suppression of CTLs and their induction of Foxp3(+) regulatory T cells. However, alpha-galactosylceramide-loaded MDSCs did not suppress CD4(+) and CD8(+) T cells and allowed for the generation of Ag-specific CTL immunity without increasing the generation of regulatory T cells. Furthermore, stimulation with activated NKT cells induced changes on MDSCs in phenotypical or maturation markers, including CD11b, CD11c, and CD86. Taken together, these findings suggest that NKT cells facilitate the conversion of immunosuppressive MDSCs into immunogenic APCs, eliciting successful antitumor immunity and providing the basis for alternative cell-based vaccines.
Abstract α-Galactosylceramide (α-GalCer), originally isolated from a marine sponge, was known to activate natural killer T (NKT) cells through CD1d-mediated Ag presentation and induce Th1 and/or Th2 ...immunity. In this study, we evaluated the nasal adjuvanticity of α-GalCer when co-administered with formalin-inactivated influenza virus A/PR/8/34 (PR8) in BALB/c mice. A single nasal immunization of inactivated PR8 and α-GalCer induced brisk levels of PR8-specific IgG and IgA Abs in serum and lung washes. Antigen-specific Ab responses lasted for 3 months, providing protective immunity against challenge with live PR8. In addition, mice given α-GalCer also exhibited cellular immune responses including cytotoxic T lymphocyte (CTL) generation. Because it did not redirect Ags into brain, α-GalCer would likely pose no risk if administered as a nasal adjuvant. These results suggest for the first time that a single nasal immunization of inactivated virus and α-GalCer is a safe and effective means of preventing influenza infection.
Carcinoembryonic antigen (CEA) is a well‐known tumor antigen that is found in the serum of patients with various cancers and is correlated with an increased risk of cancer recurrence and metastasis. ...To understand the tumor environment and to develop antitumor therapies, CEA has been studied as an antigen to activate/tolerate specific T cells. In this study, we show that CEA can function as a coinhibitory molecule and can inhibit the activation of human peripheral blood mononucleated cell‐derived T cells. The addition of CEA‐overexpressing tumor cells or immobilized CEA dampened both cell proliferation and the expression of IL‐2 and CD69 expression in T cells after TCR stimulation. The phosphorylation of ERK and translocation of NFAT were hampered in these cells, whereas the phosphorylation of proximal TCR signaling molecules such as ZAP70 and phospholipase Cγ was not affected by immobilized CEA. To determine the relevance of carcinoembryonic antigen‐related cell adhesion molecule‐1 and Src homology region 2 domain‐containing phosphatase (SHP) molecules to CEA‐mediated suppression, we tested the effect of the SHP inhibitor, NSC‐87877, on CEA‐mediated suppression of T cells; however, it did not reverse the effect of CEA. Collectively, these results indicate that CEA can function as a modulator of T‐cell responses suggesting a novel mechanism of tumor evasion.
What's new?
Carcinoembryonic antigen (CEA) is found in the serum of patients with various cancers and is correlated with an increased risk of cancer recurrence and metastasis. To shed light on the influence of CEA on T cells, here the authors investigate the co‐inhibitory role of CEA during human T cell stimulation by TCR engagement. They show that CEA‐overexpressing tumor cells or multimeric CEA significantly inhibit T cell activation, proliferation, and cytokine production. Collectively, the data suggest that multimeric CEA, such as cell‐associated CEA, can hinder T cell stimulation upon TCR engagement, which may contribute to an immune escape mechanism for tumors.
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