bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–05–21
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Senescent CD8+ T cells acquire NK cell-like innate functions to promote antitumor immunity.
  2. Linking asymmetric cell division, CD8+ T cell fate, and signal strength.
  3. Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer.
  4. Immunosenescence: molecular mechanisms and diseases.
  5. Elderly CD8+ T cells in the focus for immunotherapeutic approaches.
  6. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1.
  7. Orthogonal CRISPR screens to identify transcriptional and epigenetic regulators of human CD8 T cell function.
  8. Commentary: T cell metabolism: a new perspective on Th17/Treg cell imbalance in systemic lupus erythematosus.
  9. The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.
  10. The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism.
  11. IFNγ Transcribed by IRF1 in CD4+ Effector Memory T Cells Promotes Senescence-Associated Pulmonary Fibrosis.
  12. Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.
  13. Old T cells pollute with mito-litter.
  14. CD38: an ecto-enzyme with functional diversity in T cells.
  15. Zbp1 gene: a modulator of multiple aging hallmarks as potential therapeutic target for age-related diseases.
  16. PTEN-induced kinase 1 is associated with renal aging, via the cGAS-STING pathway.
  17. Asymmetric cell division safeguards memory CD8 T cell development.
  1. Cancer Sci. 2023 Apr 25.
    Senescent CD8+ T cells acquire NK cell-like innate functions to promote antitumor immunity.
    Toshio Kakuda, Junpei Suzuki, Yuko Matsuoka, Tadahiko Kikugawa, Takashi Saika, Masakatsu Yamashita.
      It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8+ T cells. Furthermore, Menin-deficient CD8+ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.
    Keywords:  Menin; T-cell innate functions; antigen-independent cytotoxicity; immunosenescence; senescent CD8+ T cells
    DOI:  https://doi.org/10.1111/cas.15824
  2. Cell Rep. 2023 May 12. pii: S2211-1247(23)00559-4. [Epub ahead of print]42(5): 112548
    Linking asymmetric cell division, CD8+ T cell fate, and signal strength.
    Jyoti Pokharel, Carmen Gerlach.
      Through live imaging of CD8+ T cells carrying a fate reporter, Gräbnitz et al. directly linked (a)symmetric division to T cell fate.1 Asymmetry during the first division ensured the generation of stem-like CD8+ T cells following strong T cell stimulation.
    DOI:  https://doi.org/10.1016/j.celrep.2023.112548
  3. Cancer Res. 2023 May 17. pii: CAN-22-3042. [Epub ahead of print]
    Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer.
    Xiaowen Huang, Tiantian Sun, Jilin Wang, Xialu Hong, Huimin Chen, Tingting Yan, Chengbei Zhou, Danfeng Sun, Chen Yang, TaChung Yu, Wenyu Su, Wan Du, Hua Xiong.
      Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating anti-tumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer (CRC). Herein, using single-cell RNA sequencing, we showed that metformin remodels the immune landscape of CRC. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the CRC tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in CRC cells and increased in CD8+ T cells. Untreated CRC cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T cell function. Metformin in turn reduced tryptophan uptake by CRC cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in CRC cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3042
  4. Signal Transduct Target Ther. 2023 May 13. 8(1): 200
    Immunosenescence: molecular mechanisms and diseases.
    Zaoqu Liu, Qimeng Liang, Yuqing Ren, Chunguang Guo, Xiaoyong Ge, Libo Wang, Quan Cheng, Peng Luo, Yi Zhang, Xinwei Han.
      Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells, and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging. Although the underlying molecular mechanisms remain to be addressed, it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence. Potential counteractive measures will be discussed, including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence. In recent years, immunosenescence has attracted increasing attention for its role in tumor development. As a result of the limited participation of elderly patients, the impact of immunosenescence on cancer immunotherapy is unclear. Despite some surprising results from clinical trials and drugs, it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.
    DOI:  https://doi.org/10.1038/s41392-023-01451-2
  5. Aging (Albany NY). 2023 May 18. undefined
    Elderly CD8+ T cells in the focus for immunotherapeutic approaches.
    Annette Lis, Dorina Zöphel.
      
    Keywords:  CD8 T cells +; aging; cytotoxicity; immunotherapy
    DOI:  https://doi.org/10.18632/aging.204747
  6. Nat Rev Immunol. 2023 Apr 25.
    Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1.
    Kenji Chamoto, Tomonori Yaguchi, Masaki Tajima, Tasuku Honjo.
      PD1 was originally discovered in 1992 as a molecule associated with activation-induced cell death in T cells. Over the past 30 years, it was found that PD1 has a critical role in avoiding overactivation-induced cell death and autoimmunity, whereas its inhibition unleashes anticancer immunity. Here, we outline the journey from the discovery of PD1 to its role as a breakthrough target in cancer immunotherapy. We describe its regulation and function and examine how a mechanistic understanding of PD1 signalling suggests a central function in setting the T cell activation threshold, thereby controlling T cell proliferation, differentiation, exhaustion and metabolic status. This threshold theory, in combination with new insights into T cell metabolism and a better understanding of immune cell modulation by the microbiota, can provide guidance for the development of efficient combination therapies. Moreover, we discuss the mechanisms underlying immune-related adverse events after PD1-targeted therapy and their possible treatment.
    DOI:  https://doi.org/10.1038/s41577-023-00867-9
  7. bioRxiv. 2023 May 01. pii: 2023.05.01.538906. [Epub ahead of print]
    Orthogonal CRISPR screens to identify transcriptional and epigenetic regulators of human CD8 T cell function.
    Sean R McCutcheon, Adam M Swartz, Michael C Brown, Alejandro Barrera, Christian McRoberts Amador, Keith Siklenka, Lucas Humayun, James M Isaacs, Timothy E Reddy, Smita Nair, Scott Antonia, Charles A Gersbach.
      The clinical response to adoptive T cell therapies is strongly associated with transcriptional and epigenetic state. Thus, technologies to discover regulators of T cell gene networks and their corresponding phenotypes have great potential to improve the efficacy of T cell therapies. We developed pooled CRISPR screening approaches with compact epigenome editors to systematically profile the effects of activation and repression of 120 transcription factors and epigenetic modifiers on human CD8+ T cell state. These screens nominated known and novel regulators of T cell phenotypes with BATF3 emerging as a high confidence gene in both screens. We found that BATF3 overexpression promoted specific features of memory T cells such as increased IL7R expression and glycolytic capacity, while attenuating gene programs associated with cytotoxicity, regulatory T cell function, and T cell exhaustion. In the context of chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. CAR T cells overexpressing BATF3 significantly outperformed control CAR T cells in both in vitro and in vivo tumor models. Moreover, we found that BATF3 programmed a transcriptional profile that correlated with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens with and without BATF3 overexpression to define co-factors and downstream factors of BATF3, as well as other therapeutic targets. These screens pointed to a model where BATF3 interacts with JUNB and IRF4 to regulate gene expression and illuminated several other novel targets for further investigation.
    DOI:  https://doi.org/10.1101/2023.05.01.538906
  8. Front Immunol. 2023 ;14 1164761
    Commentary: T cell metabolism: a new perspective on Th17/Treg cell imbalance in systemic lupus erythematosus.
    Jiamei Jin, Xiaogu Liu.
      
    Keywords:  T helper 17 cells; cell metabolism; fatty acid oxidation; regulatory T cells; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2023.1164761
  9. Front Immunol. 2023 ;14 1172931
    The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.
    Shonik Ganjoo, Priti Gupta, Halil Ibrahim Corbali, Selene Nanez, Thomas S Riad, Lisa K Duong, Hampartsoum B Barsoumian, Fatemeh Masrorpour, Hong Jiang, James W Welsh, Maria Angelica Cortez.
      Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.
    Keywords:  T cell; cancer; immunotherapy; metabolism; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1172931
  10. iScience. 2023 May 19. 26(5): 106683
    The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism.
    Roman Istomine, Tho-Alfakar Al-Aubodah, Fernando Alvarez, Jacob A Smith, Carston Wagner, Ciriaco A Piccirillo.
      CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.
    Keywords:  Biological sciences; Immunology; Molecular biology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2023.106683
  11. Aging Dis. 2023 Mar 23.
    IFNγ Transcribed by IRF1 in CD4+ Effector Memory T Cells Promotes Senescence-Associated Pulmonary Fibrosis.
    Haiyun Chen, Qiuyi Wang, Jie Li, Yuan Li, Ao Chen, Jiawen Zhou, Jingyu Zhao, Zhiyuan Mao, Zihao Zhou, Jin'ge Zhang, Yue Wang, Rong Wang, Qing Li, Yongjie Zhang, Runqiu Jiang, Dengshun Miao, Jianliang Jin.
      Physiologically aged lungs are prone to senescence-associated pulmonary diseases (SAPD). This study aimed to determine the mechanism and subtype of aged T cells affecting alveolar type II epithelial (AT2) cells, which promote the pathogenesis of senescence-associated pulmonary fibrosis (SAPF). Cell proportions, the relationship between SAPD and T cells, and the aging- and senescence-associated secretory phenotype (SASP) of T cells between young and aged mice were analyzed using lung single-cell transcriptomics. SAPD was monitored by markers of AT2 cells and found to be induced by T cells. Furthermore, IFNγ signaling pathways were activated and cell senescence, SASP, and T cell activation were shown in aged lungs. Physiological aging led to pulmonary dysfunction and TGF-β1/IL-11/MEK/ERK (TIME) signaling-mediated SAPF, which was induced by senescence and SASP of aged T cells. Especially, IFNγ was produced by the accumulated CD4+ effector memory T (TEM) cells in the aged lung. This study also found that physiological aging increased pulmonary CD4+ TEM cells, IFNγ was produced mainly by CD4+ TEM cells, and pulmonary cells had increased responsiveness to IFNγ signaling. Specific regulon activity was increased in T cell subclusters. IFNγ transcriptionally regulated by IRF1 in CD4+ TEM cells promoted the epithelial-to-mesenchymal transition by activating TIME signaling and cell senescence of AT2 cells with aging. Accumulated IRF1+CD4+ TEM produced IFNγ in lung with aging and anti-IRF1 primary antibody treatment inhibited the expression of IFNγ. Aging might drive T cell differentiation toward helper T cells with developmental trajectories and enhance cell interactions of pulmonary T cells with other surrounding cells. Thus, IFNγ transcribed by IRF1 in CD4+ effector memory T cells promotes SAPF. IFNγ produced by CD4+ TEM cells in physiologically aged lungs could be a therapeutic target for preventing SAPF.
    DOI:  https://doi.org/10.14336/AD.2023.0320
  12. Cancer Lett. 2023 May 10. pii: S0304-3835(23)00174-X. [Epub ahead of print]564 216223
    Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.
    Rilan Bai, Jiuwei Cui.
      Cancer cells adapt to increasing energy and biosynthetic demands by reprogramming their metabolic pathways. Mitochondria are important organelles for the metabolic reprogramming of tumor cells. In addition to supplying energy, they play crucial roles in the survival, immune evasion, tumor progression, and treatment resistance of the hypoxic tumor microenvironment (TME) in cancer cells. With the development of the life sciences, scientists have gained an in-depth understanding of immunity, metabolism, and cancer, and numerous studies have emphasized that mitochondria are essential for tumor immune escape and the regulation of immune cell metabolism and activation. Moreover, recent evidence suggests that targeting the mitochondria-related pathway with anticancer drugs can initiate the killing of cancer cells by increasing the ability of cancer cells to be recognized by immune cells, tumor antigen presentation ability, and the anti-tumor function of immune cells. This review discusses the effects of mitochondrial morphology and function on the phenotype and function of immune cells under normal and TME conditions, the effects of mitochondrial changes in tumors and microenvironments on tumor immune escape and immune cell function, and finally focuses on the recent research progress and future challenges of novel anti-tumor immunotherapy strategies targeting mitochondria.
    Keywords:  Immune regulation; Immunotherapy; Mitochondria; Neoplasm; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216223
  13. Nat Aging. 2023 May;3(5): 475-476
    Old T cells pollute with mito-litter.
    Manuel M Gómez de Las Heras, María Mittelbrunn.
      
    DOI:  https://doi.org/10.1038/s43587-023-00412-2
  14. Front Immunol. 2023 ;14 1146791
    CD38: an ecto-enzyme with functional diversity in T cells.
    Alip Ghosh, Arshi Khanam, Krishanu Ray, Poonam Mathur, Ananya Subramanian, Bhawna Poonia, Shyam Kottilil.
      CD38, a nicotinamide adenine dinucleotide (NAD)+ glycohydrolase, is considered an activation marker of T lymphocytes in humans that is highly expressed during certain chronic viral infections. T cells constitute a heterogeneous population; however, the expression and function of CD38 has been poorly defined in distinct T cell compartments. We investigated the expression and function of CD38 in naïve and effector T cell subsets in the peripheral blood mononuclear cells (PBMCs) from healthy donors and people with HIV (PWH) using flow cytometry. Further, we examined the impact of CD38 expression on intracellular NAD+ levels, mitochondrial function, and intracellular cytokine production in response to virus-specific peptide stimulation (HIV Group specific antigen; Gag). Naïve T cells from healthy donors showed remarkably higher levels of CD38 expression than those of effector cells with concomitant reduced intracellular NAD+ levels, decreased mitochondrial membrane potential and lower metabolic activity. Blockade of CD38 by a small molecule inhibitor, 78c, increased metabolic function, mitochondrial mass and mitochondrial membrane potential in the naïve T lymphocytes. PWH exhibited similar frequencies of CD38+ cells in the T cell subsets. However, CD38 expression increased on Gag-specific IFN-γ and TNF-α producing cell compartments among effector T cells. 78c treatment resulted in reduced cytokine production, indicating its distinct expression and functional profile in different T cell subsets. In summary, in naïve cells high CD38 expression reflects lower metabolic activity, while in effector cells it preferentially contributes to immunopathogenesis by increasing inflammatory cytokine production. Thus, CD38 may be considered as a therapeutic target in chronic viral infections to reduce ongoing immune activation.
    Keywords:  CD38; HIV; NAD+; T cells metabolism; mitochondrial function
    DOI:  https://doi.org/10.3389/fimmu.2023.1146791
  15. Biogerontology. 2023 May 18.
    Zbp1 gene: a modulator of multiple aging hallmarks as potential therapeutic target for age-related diseases.
    Mehran Radak, Hossein Fallahi.
      The Zbp1 gene has recently emerged as a potential therapeutic target for age-related diseases. Multiple studies have reported that Zbp1 plays a key role in regulating several aging hallmarks, including cellular senescence, chronic inflammation, DNA damage response, and mitochondrial dysfunction. Regarding cellular senescence, Zbp1 appears to regulate the onset and progression of senescence by controlling the expression of key markers such as p16INK4a and p21CIP1/WAF1. Similarly, evidence suggests that Zbp1 plays a role in regulating inflammation by promoting the production of pro-inflammatory cytokines, such as IL-6 and IL-1β, through activation of the NLRP3 inflammasome. Furthermore, Zbp1 seems to be involved in the DNA damage response, coordinating the cellular response to DNA damage by regulating the expression of genes such as p53 and ATM. Additionally, Zbp1 appears to regulate mitochondrial function, which is crucial for energy production and cellular homeostasis. Given the involvement of Zbp1 in multiple aging hallmarks, targeting this gene represents a potential strategy to prevent or treat age-related diseases. For example, inhibiting Zbp1 activity could be a promising approach to reduce cellular senescence and chronic inflammation, two critical hallmarks of aging associated with various age-related diseases. Similarly, modulating Zbp1 expression or activity could also improve DNA damage response and mitochondrial function, thus delaying or preventing the development of age-related diseases. Overall, the Zbp1 gene appears to be a promising therapeutic target for age-related diseases. In the current review, we have discussed the molecular mechanisms underlying the involvement of Zbp1 in aging hallmarks and proposed to develop effective strategies to target this gene for therapeutic purposes.
    Keywords:  Aging hallmarks; Cellular senescence; Chronic inflammation; DNA damage response; Mitochondrial dysfunction; Therapeutic target; Zbp1 gene
    DOI:  https://doi.org/10.1007/s10522-023-10039-w
  16. Aging Cell. 2023 May 15. e13865
    PTEN-induced kinase 1 is associated with renal aging, via the cGAS-STING pathway.
    Min Heui Ha, Man S Kim, Hyun-Ju An, Min-Ji Sung, Yu Ho Lee, Dong-Ho Yang, Sang Hyun Jung, Jihyun Baek, Yueun Choi, Deanne M Taylor, Yuanchao Zhang, So-Young Lee, Hye Yun Jeong.
      Mitochondrial dysfunction is considered to be an important mediator of the pro-aging process in chronic kidney disease, which is continuously increasing worldwide. Although PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, its role in renal aging remains unclear. We investigated the association between PINK1 and renal aging, especially through the cGAS-STING pathway, which is known to result in an inflammatory phenotype. Pink1 knockout (Pink1-/- ) C57BL/6 mice and senescence-induced renal tubular epithelial cells (HKC-8) treated with H2 O2 were used as the renal aging models. Extensive analyses at transcriptomic-metabolic levels have explored changes in mitochondrial function in PINK1 deficiency. To investigate whether PINK1 deficiency affects renal aging through the cGAS-STING pathway, we explored their expression levels in PINK1 knockout mice and senescence-induced HKC-8 cells. PINK1 deficiency enhances kidney fibrosis and tubular injury, and increases senescence and the senescence-associated secretory phenotype (SASP). These phenomena were most apparent in the 24-month-old Pink1-/- mice and HKC-8 cells treated with PINK1 siRNA and H2 O2 . Gene expression analysis using RNA sequencing showed that PINK1 deficiency is associated with increased inflammatory responses, and transcriptomic and metabolomic analyses suggested that PINK1 deficiency is related to mitochondrial metabolic dysregulation. Activation of cGAS-STING was prominent in the 24-month-old Pink1-/- mice. The expression of SASPs was most noticeable in senescence-induced HKC-8 cells and was attenuated by the STING inhibitor, H151. PINK1 is associated with renal aging, and mitochondrial dysregulation by PINK1 deficiency might stimulate the cGAS-STING pathway, eventually leading to senescence-related inflammatory responses.
    Keywords:  PINK1; STING; chronic kidney disease; mitochondria; renal aging
    DOI:  https://doi.org/10.1111/acel.13865
  17. Cell Rep. 2023 May 12. pii: S2211-1247(23)00479-5. [Epub ahead of print]42(5): 112468
    Asymmetric cell division safeguards memory CD8 T cell development.
    Fabienne Gräbnitz, Dominique Stark, Danielle Shlesinger, Anthony Petkidis, Mariana Borsa, Alexander Yermanos, Andreas Carr, Niculò Barandun, Arne Wehling, Miroslav Balaz, Timm Schroeder, Annette Oxenius.
      The strength of T cell receptor (TCR) stimulation and asymmetric distribution of fate determinants are both implied to affect T cell differentiation. Here, we uncover asymmetric cell division (ACD) as a safeguard mechanism for memory CD8 T cell generation specifically upon strong TCR stimulation. Using live imaging approaches, we find that strong TCR stimulation induces elevated ACD rates, and subsequent single-cell-derived colonies comprise both effector and memory precursor cells. The abundance of memory precursor cells emerging from a single activated T cell positively correlates with first mitosis ACD. Accordingly, preventing ACD by inhibition of protein kinase Cζ (PKCζ) during the first mitosis upon strong TCR stimulation markedly curtails the formation of memory precursor cells. Conversely, no effect of ACD on fate commitment is observed upon weak TCR stimulation. Our data provide relevant mechanistic insights into the role of ACD for CD8 T cell fate regulation upon different activation conditions.
    Keywords:  CD8 T cell differentiation; CD8 T cell memory; CP: Cell biology; CP: Immunology; T cell receptor signaling strength; asymmetric cell division; fate diversification; lineage tracing; single cell tracking
    DOI:  https://doi.org/10.1016/j.celrep.2023.112468
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