bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–09–29
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
  2. Metabolic footprint and logic through the T cell life cycle.
  3. Mitochondrial tonic for adoptive T cell therapies.
  4. The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.
  5. Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
  6. Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
  7. Impact of aging on the frequency, phenotype, and function of CD4+ T cells in the human female reproductive tract.
  8. DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells.
  9. Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma.
  10. Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.
  11. RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity.
  12. Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults.
  13. Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.
  14. CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane.
  1. Res Sq. 2024 Sep 16. pii: rs.3.rs-4875322. [Epub ahead of print]
    Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
    Peter McGuire, Tatiana Tarasenko, Emily Warren, Amanda Fuchs, Bharati Singh, Jose Marin, Marten Szibor.
      T cell activation, proliferation, and differentiation are fundamentally driven by shifts in cellular metabolism, with mitochondria playing a central role. Cytochrome c oxidase (COX, complex IV) is a key player in this process, as its activity is crucial for apoptosis, mtDNA maintenance, mitochondrial transcription, and mitochondrial respiration (MR), all of which influence T cell fate and function. Despite its known roles, the specific functions of COX required for T cell activity in vivo remain unclear. To isolate the role of MR in T cell function, we reintroduced this capability in COX-deficient T cells using an alternative oxidase (AOX) from Ciona intestinalis. Our findings demonstrate that MR is vital for maintaining metabolic balance during T cell activation by alleviating electron pressure from metabolic reprogramming and preserving redox homeostasis. We further showed that AOX mitigates apoptosis, prevents metabolic disruptions in glycolysis and the tricarboxylic acid cycle, and improves mtDNA maintenance and transcription, indicating that these disturbances are secondary to impaired MR in the absence of COX. Most importantly, the introduction of AOX restored robust effector and memory T cell generation and function in COX-deficient cells. These results highlight the essential role of COX-dependent MR in ensuring cellular health and underscore its pivotal role in T cell proliferation and differentiation.
    DOI:  https://doi.org/10.21203/rs.3.rs-4875322/v2
  2. Curr Opin Immunol. 2024 Sep 21. pii: S0952-7915(24)00077-3. [Epub ahead of print]91 102487
    Metabolic footprint and logic through the T cell life cycle.
    Tingting Fan, Rushil Shah, Ruoning Wang.
      A simple definition of life is a system that can self-replicate (proliferation) and self-sustain (metabolism). At the cellular level, metabolism has evolved to drive proliferation, which requires energy and building blocks to duplicate cellular biomass before division. T lymphocytes (or T cells) are required for adaptive immune responses, protecting us against invading and malignant agents capable of hyper-replication. To gain a competitive advantage over these agents, activated T cells can duplicate their biomass and divide into two daughter cells in as short as 2-6 hours, considered the fastest cell division among all cell types in vertebrates. Thus, the primary task of cellular metabolism has evolved to commit available resources to drive T cell hyperproliferation. Beyond that, the T cell life cycle involves an ordered series of fate-determining events that drive cells to transition between discrete cell states. At the life stages not involved in hyperproliferation, T cells engage metabolic programs that are more flexible to sustain viability and maintenance and sometimes are fine-tuned to support specific cellular activities. Here, we focus on the central carbon metabolism, which is most relevant to cell proliferation. We provide examples of how the changes in the central carbon metabolism may or may not change the fate of T cells and further explore a few conceptual frameworks, such as metabolic flexibility, the Goldilocks Principle, overflow metabolism, and effector-signaling metabolites, in the context of T cell fate transitions.
    DOI:  https://doi.org/10.1016/j.coi.2024.102487
  3. Nat Rev Immunol. 2024 Sep 20.
    Mitochondrial tonic for adoptive T cell therapies.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01095-5
  4. Nature. 2024 Sep 25.
    The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.
    Bing Feng, Zhiliang Bai, Xiaolei Zhou, Yang Zhao, Yu-Qing Xie, Xinyi Huang, Yang Liu, Tom Enbar, Rongrong Li, Yi Wang, Min Gao, Lucia Bonati, Mei-Wen Peng, Weilin Li, Bo Tao, Mélanie Charmoy, Werner Held, J Joseph Melenhorst, Rong Fan, Yugang Guo, Li Tang.
      Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc-IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc-IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc-IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.
    DOI:  https://doi.org/10.1038/s41586-024-07962-4
  5. Sci Immunol. 2024 Sep 20. 9(99): eadp3475
    Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
    Darren R Heintzman, Rachael C Sinard, Emilie L Fisher, Xiang Ye, Andrew R Patterson, Joel H Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J Rodriguez-Garcia, Nowrin U Chowdhury, Emily N Arner, Evan S Krystoviak, Frank M Mason, Yasmine T Toudji, KayLee K Steiner, Wasay Khan, Lana M Olson, Angela L Jones, Hanna S Hong, Lindsay Bass, Katherine L Beier, Wentao Deng, Costas A Lyssiotis, Dawn C Newcomb, Alexander G Bick, W Kimryn Rathmell, John T Wilson, Jeffrey C Rathmell.
      Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.
    DOI:  https://doi.org/10.1126/sciimmunol.adp3475
  6. Nat Immunol. 2024 Oct;25(10): 1884-1899
    Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
    Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.
      TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.
    DOI:  https://doi.org/10.1038/s41590-024-01963-1
  7. Front Immunol. 2024 ;15 1465124
    Impact of aging on the frequency, phenotype, and function of CD4+ T cells in the human female reproductive tract.
    Zheng Shen, Landon G Vom Steeg, Mickey V Patel, Marta Rodriguez-Garcia, Charles R Wira.
      Since CD4+ T cells are essential for regulating adaptive immune responses and for long lasting mucosal protection, changes in CD4+ T cell numbers and function are likely to affect protective immunity. What remains unclear is whether CD4+ T cell composition and function in the female reproductive tract (FRT) changes as women age. Here we investigated the changes in the composition and function of CD4+ T cells in the endometrium (EM), endocervix (CX), and ectocervix (ECX) with aging. We observed a significant decrease in both the total number and percentage of CD4+ T cells in the EM with increasing age, particularly in the years following menopause. CD4+ T cells within the FRT predominantly expressed CD69. The proportion of CD69+CD4+ T cells increased significantly with increasing age in the EM, CX and ECX. The composition of T helper cell subsets within the EM CD4+ T cell population also showed age-related changes. Specifically, there was a significant increase in the proportion of Th1 cells and a significant decrease in Th17 and Treg cells with increasing age. Furthermore, the production of IFNγ by CD4+ T cells in the EM, CX, and ECX significantly decreased with increasing age upon activation. Our findings highlight the complex changes occurring in CD4+ T cell frequency, phenotype, and function within the FRT as women age. Understanding these age-related immune changes in the FRT is crucial for enhancing our knowledge of reproductive health and immune responses in women.
    Keywords:  CD4+ T cells; aging; cytokine production; human female reproductive tract; menopause; tissue resident memory phenotype T cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1465124
  8. PLoS Pathog. 2024 Sep 26. 20(9): e1012581
    DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells.
    Zheng Yu, Varun Sasidharan-Nair, Thalea Buchta, Agnes Bonifacius, Fawad Khan, Beate Pietzsch, Hosein Ahmadi, Michael Beckstette, Jana Niemz, Philipp Hilgendorf, Philip Mausberg, Andreas Keller, Christine Falk, Dirk H Busch, Kilian Schober, Luka Cicin-Sain, Fabian Müller, Melanie M Brinkmann, Britta Eiz-Vesper, Stefan Floess, Jochen Huehn.
      Epigenetic mechanisms stabilize gene expression patterns during CD8+ T cell differentiation. Although adoptive transfer of virus-specific T cells is clinically applied to reduce the risk of virus infection or reactivation in immunocompromised individuals, the DNA methylation pattern of virus-specific CD8+ T cells is largely unknown. Hence, we here performed whole-genome bisulfite sequencing of cytomegalovirus-specific human CD8+ T cells and found that they display a unique DNA methylation pattern consisting of 79 differentially methylated regions (DMRs) when compared to memory CD8+ T cells. Among the top demethylated DMRs in cytomegalovirus-specific CD8+ T cells was TBKBP1, coding for TBK-binding protein 1 that can interact with TANK-binding kinase 1 (TBK1) and mediate pro-inflammatory responses in innate immune cells downstream of intracellular virus sensing. Since TBKBP1 has not yet been reported in T cells, we aimed to unravel its role in virus-specific CD8+ T cells. TBKBP1 demethylation in terminal effector CD8+ T cells correlated with higher TBKBP1 expression at both mRNA and protein level, independent of alternative splicing of TBKBP1 transcripts. Notably, the distinct DNA methylation patterns in CD8+ T cell subsets was stable upon long-term in vitro culture. TBKBP1 overexpression resulted in enhanced TBK1 phosphorylation upon stimulation of CD8+ T cells and significantly improved their virus neutralization capacity. Collectively, our data demonstrate that TBKBP1 modulates virus-specific CD8+ T cell responses and could be exploited as therapeutic target to improve adoptive T cell therapies.
    DOI:  https://doi.org/10.1371/journal.ppat.1012581
  9. iScience. 2024 Sep 20. 27(9): 110863
    Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma.
    Sho Yoshimoto, Ayano Kudo, Antonia Rotolo, Kay Foos, Lauren Olenick, Satoshi Takagi, Nicola J Mason.
      Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical outcomes in patients with relapsed/refractory B cell leukemias; however, response rates in patients with large B cell lymphoma (LBCL) are less impressive. Expression of PD-1 on activated T cells and PD-L1 on malignant, stromal, and immune cells within the tumor microenvironment (TME) contribute to CAR-T exhaustion, hypofunction, and treatment failures. Here, a comparative approach is taken to develop a chimeric switch receptor (CSR) with potential to augment CAR-T persistence, function, and clinical efficacy in immune competent, pet dogs with spontaneous B cell lymphoma (BCL). We show that similar to human CAR-T cells, expression of a PD-1/CD28 CSR in canine CAR-T cells results in enhanced function against PD-L1+ targets and preserves central memory phenotype. We also demonstrate that these effects depend upon active CSR signaling. This work paves the way for in vivo studies in canine BCL patients to inform human trial design.
    Keywords:  Cancer; Therapeutics; Veterinary medicine
    DOI:  https://doi.org/10.1016/j.isci.2024.110863
  10. Nat Metab. 2024 Sep 25.
    Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.
    Shi-Long Zhang, Xin Wang, Qing-Qing Cai, Chen Chen, Zheng-Yan Zhang, Ya-Yun Xu, Meng-Xuan Yang, Qing-An Jia, Yan Wang, Zhi-Ming Wang.
      The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s42255-024-01137-1
  11. EMBO Mol Med. 2024 Sep 25.
    RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity.
    Xiaobing Duan, Jiali Hu, Yuncong Zhang, Xiaoguang Zhao, Mingqi Yang, Taoping Sun, Siya Liu, Xin Chen, Juan Feng, Wenting Li, Ze Yang, Yitian Zhang, Xiaowen Lin, Dingjie Liu, Ya Meng, Guang Yang, Qiuping Lin, Guihai Zhang, Haihong Lei, Zhengsheng Yi, Yanyan Liu, Xiaobing Liang, Yujuan Wu, Wenqing Diao, Zesong Li, Haihai Liang, Meixiao Zhan, Hong-Wei Sun, Xian-Yang Li, Ligong Lu.
      Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.
    Keywords:  AKT/Glycolysis Signalling Pathway; CD8+ T cells; Immune Checkpoint; Immunotherapy; RIG-I
    DOI:  https://doi.org/10.1038/s44321-024-00136-9
  12. bioRxiv. 2024 Sep 14. pii: 2024.09.10.612119. [Epub ahead of print]
    Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults.
    Qiuyu Gong, Mehul Sharma, Emma L Kuan, Marla C Glass, Aishwarya Chander, Mansi Singh, Lucas T Graybuck, Zachary J Thomson, Christian M LaFrance, Samir Rachid Zaim, Tao Peng, Lauren Y Okada, Palak C Genge, Katherine E Henderson, Elisabeth M Dornisch, Erik D Layton, Peter J Wittig, Alexander T Heubeck, Nelson M Mukuka, Julian Reading, Charles R Roll, Veronica Hernandez, Vaishnavi Parthasarathy, Tyanna J Stuckey, Blessing Musgrove, Elliott Swanson, Cara Lord, Morgan D A Weiss, Cole G Phalen, Regina R Mettey, Kevin J Lee, John B Johanneson, Erin K Kawelo, Jessica Garber, Upaasana Krishnan, Megan Smithmyer, E John Wherry, Laura Vella, Sarah E Henrickson, Mackenzie S Kopp, Adam K Savage, Lynne A Becker, Paul Meijer, Ernest M Coffey, Jorg J Goronzy, Cate Speake, Thomas F Bumol, Ananda W Goldrath, Troy R Torgerson, Xiao-Jun Li, Peter J Skene, Jane H Buckner, Claire E Gustafson.
      The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults' memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.
    DOI:  https://doi.org/10.1101/2024.09.10.612119
  13. bioRxiv. 2024 Sep 13. pii: 2024.08.19.608538. [Epub ahead of print]
    Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.
    Sarah Staudt, Fabian Nikolka, Markus Perl, Julia Franz, Noemie Leblay, Xiaoli-Kat Yuan, Linda Warmuth, Matthias A Fantes, Aiste Skorpskaite, Teng Fei, Maria Bromberg, Patxi San Martin-Uriz, Juan Roberto Rodriguez-Madoz, Kai Ziegler-Martin, Nazdar Adil-Gholam, Pascal Benz, Phuc Tran Huu, Christoph Stein-Thoeringer, Michael Schmitt, Karin Kleigrewe, Fabian Freitag, Zeno Riester, Justus Weber, Kira Mangold, Hermann Einsele, Felipe Prosper, Wilfried Ellmeier, Dirk Busch, Alexander Visekruna, John Slingerland, Roni Shouval, Karsten Hiller, Marcel van den Brink, Patrick Pausch, Paola Neri, Michael Hudecek, Hendrik Poeck, Maik Luu.
      Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro, in vivo challenge showed inferior tumor control. Metabolic tracing of 13C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications.
    DOI:  https://doi.org/10.1101/2024.08.19.608538
  14. Nat Commun. 2024 Sep 27. 15(1): 8304
    CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane.
    Eri Katsuyama, Morgane Humbel, Abel Suarez-Fueyo, Abhigyan Satyam, Nobuya Yoshida, Vasileios C Kyttaris, Maria G Tsokos, George C Tsokos.
      CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4+ T cell function. Using primary human T cells and CD38-sufficient and CD38-deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca2+ flux through the PLCγ1-IP3 pathway. Interestingly, correction of the calcium overload by an IP3 receptor inhibitor, but not by a store-operated calcium entry (SOCE) inhibitor, improves IL-2 production by CD4+ T cells in SLE. This study demonstrates that CD38 affects calcium homeostasis in CD4+ T cells by controlling cell membrane lipid composition that results in suppressed IL-2 production. CD38 inhibition with biologics or small drugs should be expected to benefit patients with SLE.
    DOI:  https://doi.org/10.1038/s41467-024-52617-7
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