Taa Cells and Granzyme K: Old Players with New Tricks
2021; Cell Press; Volume: 54; Issue: 1 Linguagem: Inglês
10.1016/j.immuni.2020.12.008
ISSN1097-4180
Autores Tópico(s)Single-cell and spatial transcriptomics
ResumoInflammaging is associated with chronic diseases, but tissue-specific changes in the immune system remain unknown. In this issue of Immunity, Mogilenko et al. use single-cell RNA sequencing, flow cytometry, and mass cytometry to describe age-related differences, including the accumulation of age-associated T cells that contribute to inflammaging. Inflammaging is associated with chronic diseases, but tissue-specific changes in the immune system remain unknown. In this issue of Immunity, Mogilenko et al. use single-cell RNA sequencing, flow cytometry, and mass cytometry to describe age-related differences, including the accumulation of age-associated T cells that contribute to inflammaging. Inflammaging, originally described by Dr. Claudio Franceschi, indicates the increase in inflammation that is an increased risk factor for both morbidity and mortality during aging (Franceschi et al., 2018Franceschi C. Zaikin A. Gordleeva S. Ivanchenko M. Bonifazi F. Storci G. Bonafè M. Inflammaging 2018: An update and a model.Semin. Immunol. 2018; 40: 1-5Crossref PubMed Scopus (39) Google Scholar). Initially, the concept focused on the systemic rise in traditional inflammatory factors, including tumor necrosis factor-a (TNFα), interleukin-6 (IL-6), and C-Reactive Protein (CRP), but now extends to encompass global changes in the immune system and the alterations that occur with age in tissue resident immune cells. There are many potential triggers of inflammaging, including pathogens, endogenous cellular debris, damaged macromolecules, epigenetic changes, and nutrients. It is thought that continuous encounters of such triggers lead to low-grade inflammatory activation that can ultimately cause age-related metabolic disease, cancer, or neurogenerative disease. Although greater understanding surrounding the potential of aged tissue resident immune cells to drive tissue dysfunction or increased vulnerability to multiple diseases has developed, many questions surrounding the precise changes in tissue resident immune cells still exist. In this issue, Mogilenko et al., 2020Mogilenko D.A. Shpynov O. Andhey P.S. Arthur L. Swain A. Esaulova E. Brioschi S. Shchukina I. Kerndl M. Bambouskova M. et al.Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging.Immunity. 2020; 54 (this issue): 99-115Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar have used single-cell RNA sequencing, mass cytometry, and flow cytometry to broadly evaluate age-related changes in immune cell populations across multiple tissues. In addition to tissue-specific changes in the immune cell populations, the authors identified a multi-tissue accumulation of a newly identified population of age-associated T cells (CD8+ PD1+ Granzyme K+ TOX+ cells; termed Taa cells) in both humans and mice. While the precise function and mechanism of accumulation for most aged immune cell subsets remain to be defined, the authors show that the aged environment drive Taa cell accumulation where they promote inflammaging through their secretion of Granzyme K (Figure 1) (Mogilenko et al., 2020Mogilenko D.A. Shpynov O. Andhey P.S. Arthur L. Swain A. Esaulova E. Brioschi S. Shchukina I. Kerndl M. Bambouskova M. et al.Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging.Immunity. 2020; 54 (this issue): 99-115Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). The authors identified Taa cells as memory cells with a higher level of clonal diversity as compared to other effector memory CD8+ T cells in aged tissue. Historically, tissue resident memory T cells arise during viral infection and occupy tissues without recirculating to provide a first response against infection reencountered at body surfaces. Taa cells are tissue resident, but their ability to circulate is currently unclear. Intriguingly, clonally expanded Taa cells, i.e., expressing identical T cell receptors (TCRs), can be found in different tissues within the same aged animal, suggesting that they respond to age-specific antigens that are not restricted by tissue but are restricted within individual animals. Taa are a unique subset of exhausted memory cells, in that they express Programmed Death (PD)-1, a surface receptor described to be elevated on aged CD8+ T cells and TOX (Lages et al., 2010Lages C.S. Lewkowich I. Sproles A. Wills-Karp M. Chougnet C. Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway.Aging Cell. 2010; 9: 785-798Crossref PubMed Scopus (62) Google Scholar), a crucial transcription factor required for the development of exhausted T cells (Bordon, 2019Bordon Y. TOX for tired T cells.Nat. Rev. Immunol. 2019; 19: 476Crossref PubMed Scopus (7) Google Scholar). Furthermore, scATAC-seq (single-cell assay for transposase-accessible chromatin using sequencing) profiling revealed an enrichment with T-box motifs with upregulation of Eomes and downregulation of Tbx21, transcription factors that control T cell differentiation, but the transcriptional lineage of Taa cells has yet to be dissected out. The accumulation of Taa occurred in an institution-independent manner, as they were also found in publicly available datasets (Schaum et al., 2020Schaum N. Lehallier B. Hahn O. Pálovics R. Hosseinzadeh S. Lee S.E. Sit R. Lee D.P. Losada P.M. Zardeneta M.E. et al.Tabula Muris ConsortiumAgeing hallmarks exhibit organ-specific temporal signatures.Nature. 2020; 583: 596-602Crossref PubMed Scopus (48) Google Scholar). Even more intriguing, sequencing, flow cytometry characterization, and ex vivo anti-CD3 stimulation revealed that Taa cells expressed higher amounts of Granzyme K, whereas Granzyme B was not expressed. Granzymes are serine proteases stored in granules that play numerous roles in immune responses against tumors, intracellular pathogens, and virus-infected cells. Although the precise mechanism of Granzyme K action remains to be discovered, in vitro treatment with recombinant Granzyme K amplified the secretion of senescence associated secretory products (SASPs: CCL2, IL-6, CXCL1) and secretion of IFNγ-induced SASP from senescent cells. Previous publications show that Granzyme K cleaves inactive inflammatory factors to their active products and can cause single-stranded DNA nicks (Bovenschen and Kummer, 2010Bovenschen N. Kummer J.A. Orphan granzymes find a home.Immunol. Rev. 2010; 235: 117-127Crossref PubMed Scopus (67) Google Scholar); therefore, Granzyme K may have direct roles in increasing SASP factors or the senescence phenotype of aged stromal cells through inflammation or genotoxic stress. SASP secretion is a characteristic of senescent cells, which are resistant to apoptosis and unable to proliferate; however, they remain metabolically active and they accumulate during aging (Kale et al., 2020Kale A. Sharma A. Stolzing A. Desprez P.Y. Campisi J. Role of immune cells in the removal of deleterious senescent cells.Immunity & Ageing. 2020; 17Crossref PubMed Scopus (42) Google Scholar). Senescent cells amplify inflammation and drive age-related diseases, at least in part, through their SASP secretion. SASPs normally function to signal the immune system that a cell has been damaged and are intended to prevent accumulation of senescent cells. As such, depletion of senescent cells in transgenic aged mouse models or using natural senolytics in aged wild-type mice extends lifespan, reduces SASP factors, and improves health span, but whether any of the already available inhibitors against Granzyme K would be effective in preventing SASP or inflammaging has yet to be tested. Taa cells accumulated in fibronectin (FN1)-rich areas of aged tissue, likely through their expression of CD49d, which binds FN1. The aged environment drove the immune cell phenotype, as exemplified when the authors transferred naive CD8+ T cells from young mice into aged hosts, and the young cells developed the aged phenotype, including PD1, Granzyme K, and CD49d expression, consistent with their migration to the aged tissues. In contrast, adoptive transfer of aged CD8+ Taa cells into young hosts showed a stable aged phenotype. In addition to the multi-tissue (lung, liver, peritoneal cavity, and spleen) accumulation of Taa cells, there were also tissue-specific changes of various immune cell populations (Figure 1). First, there were decreases in peritoneal macrophage and lung alveolar macrophages. There were also decreases in other innate immune cells, including plasmacytoid dendritic cells (liver), conventional dendritic cells (spleen), NK cells (all organs), and innate lymphoid cells (ILC1 in liver, ILC2 in lung). Decreased frequency of innate immune cells, including macrophages, has been previously reported in adipose tissue and contributes to tissue dysfunction in an inflammaging-dependent manner (Camell et al., 2017Camell C.D. Sander J. Spadaro O. Lee A. Nguyen K.Y. Wing A. Goldberg E.L. Youm Y.H. Brown C.W. Elsworth J. et al.Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing.Nature. 2017; 550: 119-123Crossref PubMed Scopus (174) Google Scholar). B lymphocytes also showed tissue-specific changes. A population of Zbtb32+ B cells with tissue-specific characteristics were increased in the spleen (age-associated B cells identified by the Cancro lab; AABs) and peritoneal cavity (self-reactive B1 cells). Finally, sequencing of the CD4+ T cell population revealed higher proportions of FOXP3+ regulatory T (Tregs) cells in the spleen, but changes in other CD4+ T cell populations occurred across all tissues, including a decrease in naive cells, increase in effector memory, upregulation of PD1, and maintenance of TCR diversity through age. It is currently unclear as to why these immune cell changes occur in a tissue-specific manner, what the trigger that causes these changes is, and whether Taa accumulation is a part of that trigger; however, these results help underscore the power of the single-cell RNA sequencing analysis to tease out the details of age-related changes in the immune system in a systemic manner. Finally, Mogilenko et al. evaluated the aging immune system in young and old men. Of importance, some changes seen in mice were not seen in humans—notably, the composition of B cell clusters undergoes relatively little change, with the exception of a decrease in ZBTB32+ B cells that were transcriptionally similar to aged B cells (ABCs). However, clusters of CD8+ memory T cells that expressed Granzyme K, but not Granzyme B, were elevated with age. They further defined these highly clonal cells as CD57−, CD27+, and CD28+, suggesting that they may be unique from CD28− senescent cells, which are refractory to costimulation (Fagnoni et al., 1996Fagnoni F.F. Vescovini R. Mazzola M. Bologna G. Nigro E. Lavagetto G. Franceschi C. Passeri M. Sansoni P. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians.Immunology. 1996; 88: 501-507Crossref PubMed Scopus (277) Google Scholar). These results highlight the importance of analysis in aged human tissues to better understand the inflammaging model. In the inflammaging model, tissue resident innate cells, primarily macrophages, act as the cellular sensors of the initial triggers and become appropriately activated and inflamed to eliminate the threat. Through repeated exposure over time, these cells become chronically inflamed and feed forward into the inflammatory environment. The NLRP3 inflammasome is a well-described sensor in macrophages that drives inflammaging, and it recognizes a wide range of endogenous and exogenous pathogens in mice and humans (Franceschi et al., 2018Franceschi C. Zaikin A. Gordleeva S. Ivanchenko M. Bonifazi F. Storci G. Bonafè M. Inflammaging 2018: An update and a model.Semin. Immunol. 2018; 40: 1-5Crossref PubMed Scopus (39) Google Scholar). In the context of lifelong exposure to multiple pathogens that humans undergo, including those of viral origin, Taa cells may also be a physiologically relevant sensor of viral pathogens that have been previously encountered. The specific trigger that activates Taa cells is currently unknown; is it a TCR-specific antigen or some other factor? It may also be that Taa cells accumulate downstream of chronic inflammation in tissue resident innate immune cells; additional clarification on how the various immune cell subsets interact is required to fully understand their contribution to inflammaging. Now that Taa cells and Granzyme K have acquired a new skill to promote SASP and inflammaging, future research will need to determine whether they can be retrained to appropriately respond to their antigen, or whether old habits just die hard. This work was supported by National Institute of Health (NIH) grants RO1 AG063543-02S1 ( National Institute on Aging ) and R00 AG058800 (National Institute on Aging), the Medical Discovery Team on the Biology of Aging , and the Fesler-Lampert Chair in Aging Studies . The figure was created with BioRender.com. Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of InflammagingMogilenko et al.ImmunityDecember 2, 2020In BriefAging affects the immune system and establishes a chronic low-grade inflammation (inflammaging). Mogilenko et al. defined organ-specific and common alterations of immune cell populations in aging and identified a distinct subset of clonal GZMK+ CD8+ T cells as a conserved cellular hallmark of inflammaging in mice and humans. Full-Text PDF
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