Article
Multidisciplinary Sciences
Rouven Schulz, Medina Korkut-Demirbas, Gloria Colombo, Sandra Siegert
Summary: This study introduces a chemogenetic approach to study G protein-coupled receptors (GPCRs) by designing GPCR chimeras that can mimic the functions of the target receptors without knowing their immediate ligands. The researchers demonstrate the successful use of this approach in studying the beta 2-adrenergic receptor in microglia and its role in inflammation. The results show that the chimeric receptors exhibit similar responses to the endogenous receptors in terms of signaling pathways and cellular processes. This new approach allows for the investigation of cell type-specific pathways without the need for known ligands.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Mladen Jergovic, Christopher P. Coplen, Jennifer L. Uhrlaub, David G. Besselsen, Shu Cheng, Megan J. Smithey, Janko Nikolich-Zugich
Summary: Infections can lead to the expansion of a subpopulation of long-lived, Ly6C(+) CD8(+) Tn cells with accelerated effector function, depending on the action of IFN-I. This highlights the significant role of infection-driven IFN-I in regulating Tn homeostasis and function, with potential implications for immunotherapy.
NATURE COMMUNICATIONS
(2021)
Article
Immunology
Hao Sun, Frederic Lagarrigue, Hsin Wang, Zhichao Fan, Miguel Alejandro Lopez-Ramirez, John T. Chang, Mark H. Ginsberg
Summary: Integrin activation is crucial for lymphocyte trafficking and immune function. RIAM is necessary for conventional T cell integrin activation, but dispensable for regulatory T cell integrin activation and suppressive function. Inhibition of RIAM can prevent spontaneous Tconv cell-mediated autoimmune colitis while maintaining T reg cell trafficking and function.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Allergy
Tomoko Hirano, Tetsuya Honda, Shuto Kanameishi, Yuki Honda, Gyohei Egawa, Akihiko Kitoh, Saeko Nakajima, Atsushi Otsuka, Takashi Nomura, Teruki Dainichi, Tomonori Yaguchi, Takashi Inozume, Tatsuki R. Kataoka, Koji Tamada, Kenji Kabashima
Summary: The PD-1/PD-L1 pathway negatively regulates CD8(+) T cell activation in the skin through mast cells (MCs), which are found to highly express PD-L1 and play a crucial role in modulating inflammatory responses.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2021)
Article
Allergy
Cynthia Kanagaratham, Tahereh Derakhshan, Yasmeen S. El Ansari, Kameryn N. Furiness, Eleanor Hollers, Mats Keldsen, Hans C. Oettgen, Daniel F. Dwyer
Summary: In this study, the inhibitory effects of IgG:Fc?RIIb signaling on MC responses to IgE were assessed using complementary transcriptomic and functional approaches. The results showed that IgG signaling via Fc?RIIb has a suppressive effect on IgE-induced MC transcription, especially genes related to bone marrow-derived MCs activation. These findings are important for understanding the regulatory mechanisms of IgG on IgE-induced MC responses.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Immunology
Katayoun Ayasoufi, Delaney M. Wolf, Shelby L. Namen, Fang Jin, Zachariah P. Tritz, Christian K. Pfaller, Jiaying Zheng, Emma N. Goddery, Cori E. Fain, Lauren R. Gulbicki, Anna L. Borchers, Rachael A. Reesman, Lila T. Yokanovich, Mark A. Maynes, Michael A. Bamkole, Roman H. Khadka, Michael J. Hansen, Long-Jun Wu, Aaron J. Johnson
Summary: The contribution of circulating versus tissue resident memory T cells to clinical neuropathology is not well understood. This study found that tissue resident memory T cells in the brain can induce significant neuroinflammation, neuropathology, and peripheral immunosuppression. Understanding the functions of these cells is crucial in investigating their role in neurodegenerative disorders and long-term complications associated with viral infections.
BRAIN BEHAVIOR AND IMMUNITY
(2023)
Article
Multidisciplinary Sciences
Carmen Rozmanic, Berislav Lisnic, Marina Pribanic Matesic, Andrea Mihalic, Lea Hirsl, Eugene Park, Ana Lesac Brizic, Daniela Indenbirken, Ina Viduka, Marina Santic, Barbara Adler, Wayne M. Yokoyama, Astrid Krmpotic, Vanda Juranic Lisnic, Stipan Jonjic, Ilija Brizic
Summary: Infections in early life can have profound and long-lasting effects on the maturation and functionality of NK cells.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Jocelyn Karunia, Aram Niaz, Mawj Mandwie, Sarah Thomas Broome, Kevin A. Keay, James A. Waschek, Ghaith Al-Badri, Alessandro Castorina
Summary: The study demonstrated that both PACAP and VIP can attenuate microglial activation and inhibit the expression of inflammatory mediators. However, despite their similar immunosuppressive effects, the two peptides have distinct impacts on the morphology and migration capacity of microglial cells. Specifically, PACAP showed better performance in altering cell morphology and restoring impaired cell migration compared to VIP.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Xiancai Zhong, Hongmin Wu, Wencan Zhang, Yousang Gwack, Weirong Shang, Kyle O. Lee, Noah Isakov, Zhiheng He, Zuoming Sun
Summary: This research reveals that RORyt not only regulates the differentiation of TH17 cells, but also plays a role in their effector function. By mutating K256R, which prevents ubiquitination of RORyt, the distinct functions of RORyt in TH17 differentiation and effector function can be separated.
Article
Immunology
Quynh P. Nguyen, Kennidy K. Takehara, Tianda Z. Deng, Shannon O'Shea, Maximilian Heeg, Kyla D. Omilusik, J. Justin Milner, Sara Quon, Matthew E. Pipkin, Jinyong Choi, Shane Crotty, Ananda W. Goldrath
Summary: After infection, T cells differentiate into long-lived memory cells that can circulate through secondary lymphoid organs or reside in tissues. CD4+ tissue-resident memory T cells (TRM) in the small intestine (SI) responding to acute viral infection share a gene expression program and chromatin accessibility profile with circulating TH1 cells, and gradually acquire a mature TRM program. Single-cell RNA sequencing reveals heterogeneity among established CD4+ TRM, predominantly located in the lamina propria, and identifies a population of cells that coexpress both effector- and memory-associated genes. Transcriptional regulators Blimp1, Id2, and Bcl6 are required for the formation and development of CD4+ TRM in the SI. These findings provide insights into the development, differentiation, and persistence of CD4+ TRM in response to viral infection.
SCIENCE IMMUNOLOGY
(2023)
Article
Crystallography
Mengying Wang, Angelica Luana C. Barra, Hevila Brognaro, Christian Betzel
Summary: The scientific discussion about classical and nonclassical nucleation theories has been ongoing for two decades. Recent studies have focused on multiple nucleation pathways and the role of metastable intermediates in crystallization processes. By investigating a model protein and employing a pulsed electric field, the researchers discovered new insights into nucleation processes and proposed a novel experimental strategy for adjusting and facilitating crystallization.
Article
Cell Biology
Mahboobeh Amoushahi, Karin Lykke-Hartmann
Summary: Women with cancer and low ovarian reserves who undergo infertility treatment face challenges, with ovarian tissue cryopreservation being a method to preserve fertility. Activation of dormant ovarian follicles is hindered by limited understanding of molecular determinants. A study on oocytes from dormant and activated follicles showed enrichment of genes related to cell cycle and signal transduction in primary follicles and mature oocytes. Downregulation of genes related to mitochondrial and ROS production was observed in oocytes from dormant follicles, with a dynamic pattern in genes related to primordial follicle activation and oocyte maturation. The transcriptome of mature oocytes showed significant differences from oocytes of dormant and activated follicles.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biology
Juana Serrano-Lopez, Shailaja Hegde, Sachin Kumar, Josefina Serrano, Jing Fang, Ashley M. Wellendorf, Paul A. Roche, Yamileth Rangel, Leolene J. Carrington, Hartmut Geiger, H. Leighton Grimes, Sanjiv Luther, Ivan Maillard, Joaquin Sanchez-Garcia, Daniel T. Starczynowski, Jose A. Cancelas
Summary: This study reveals the rapid migration of myeloid progenitors from bone marrow to lymphatics during systemic inflammation, mediated by specific signaling pathways, which plays an anti-inflammatory role.
Article
Immunology
Shannon M. Kahan, Rakesh K. Bakshi, Jennifer T. Ingram, R. Curtis Hendrickson, Elliot J. Lefkowitz, David K. Crossman, Laurie E. Harrington, Casey T. Weaver, Allan J. Zajac
Summary: The ability to produce IL-2 identifies constituents of the expanded CD8 T cell effector pool with stem-like features, which exhibit superior protective powers. The production of IL-2 by cells attenuates the ability to receive IL-2 signals, limiting terminal effector formation and conferring superior protection. Non-producing effector cells, on the other hand, gain effector traits at the expense of memory formation. Despite distinct properties during the effector phase, IL-2-producing and non-producing CD8 T cells converge transcriptionally as memory matures, forming populations with equal recall abilities.
SCIENCE IMMUNOLOGY
(2022)
Article
Cell Biology
Milton Pereira, Danielle F. Durso, Clare E. Bryant, Evelyn A. Kurt-Jones, Neal Silverman, Douglas T. Golenbock, Ricardo T. Gazzinelli
Summary: This study examines the importance of IRAK proteins in TLR4 activation and confirms the essential role of IRAK4 kinase activity in MYD88 signaling. It also reveals the crucial role of the IRAK4 scaffold in integrating MYD88 and TRIF in TLR4 signaling.
Article
Immunology
Lyndsay Avery, Tanner F. Robertson, Christine F. Wu, Nathan H. Roy, Samuel D. Chauvin, Eric Perkey, Ashley Vanderbeck, Ivan Maillard, Janis K. Burkhardt
Summary: X-MAID is a primary immunodeficiency disease characterized by severe lymphopenia and recurrent infections. Using a mouse model, researchers found that the disease is caused by a mutation in the protein moesin. This model provides valuable insights into the complexity of immunodeficiency and the role of the actin cortex in lymphocyte function.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Oncology
Andrew W. Hahn, Ashley Menk, Dayana B. Rivadeneira, Ryan C. Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K. Mishra, Tuba N. Gide, Camelia Quek, Yan Zang, Christine N. Spencer, Alexander M. Menzies, Carrie R. Daniel, Courtney W. Hudgens, Theodore Nowicki, Lauren E. Haydu, M. A. Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M. Burton, Jared Malke, Julie M. Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E. Woodman, Y. N. Vashisht Gopal, Renato Guerrieri, Grant M. Fischer, Jian Wang, Khalida M. Wani, John F. Thompson, Jeffrey E. Lee, Patrick Hwu, Nadim Ajami, Jeffrey E. Gershenwald, Georgina Long, Richard A. Scolyer, Michael T. Tetzlaff, Alexander J. Lazar, Dirk Schadendorf, Jennifer A. Wargo, John M. Kirkwood, Ralph J. DeBerardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S. Wilmott, Weiyi Peng, Michael A. Davies, Greg M. Delgoffe, Yana G. Najjar, Jennifer L. McQuade
Summary: This study investigated the association between body mass index (BMI) and tumor or microbiome characteristics in patients with metastatic melanoma. The findings suggest that the host metabolic phenotype influences melanoma metabolism and may explain the improved outcomes observed in overweight/obese patients treated with immune checkpoint inhibitors and targeted therapies.
CLINICAL CANCER RESEARCH
(2023)
Article
Immunology
Paolo D. A. Vignali, Kristin DePeaux, McLane J. J. Watson, Chenxian Ye, B. Rhodes Ford, Konstantinos Lontos, Nicole K. K. McGaa, Nicole E. E. Scharping, Ashley V. V. Menk, Simon C. C. Robson, Amanda C. C. Poholek, Dayana B. B. Rivadeneira, Greg M. M. Delgoffe
Summary: CD8(+) T cells play a crucial role in cancer cell elimination. Exhaustion, a hypofunctional state, can be induced in these cells by factors in the tumor microenvironment (TME). Highly exhausted T (tT(ex)) cells, resistant to checkpoint blockade immunotherapy, resemble CD4(+)Foxp3(+) regulatory T cells and suppress T cell proliferation through CD39-generated immunosuppressive adenosine. Restricting CD39 in endogenous CD8(+) T cells slows tumor progression, improves immunotherapy response, and enhances infiltration of tumor-specific T cells. Induced by tumor hypoxia, CD39 expression on tT(ex) cells can be mitigated to reduce their suppressive effects. Hence, targeting or eliminating tT(ex) cells in the TME could enhance immunotherapy efficacy.
Article
Oncology
Nicole N. Scheff, Marci L. Nilsen, Jinhong Li, Alexandria L. Harris, Rajesh Acharya, Andrew Swartz, Ronan W. Hsieh, Jennifer L. Anderson, Robert L. Ferris, Ashley V. Menk, Greg M. Delgoffe, Dan P. Zandberg
Summary: This study evaluated the impact of opioids on the efficacy of immunotherapy in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients. The results showed that higher opioid dosages were associated with lower progression-free survival and overall survival, as well as lower CD8+ T cell counts in the tumor microenvironment.
Article
Oncology
Jian Ding, Sarah Guyette, Brett Schrand, Jessica Geirut, Holly Horton, Guangwu Guo, Greg Delgoffe, Ashley Menk, Patrick A. Baeuerle, Robert Hofmeister, Robert Tighe
Summary: TRuC-T cells utilize all signaling subunits of the TCR to activate T cells and effectively kill MSLN+ tumor cells, showing comparable efficacy to MSLN-targeted CAR-T cells. However, TRuC-T cells exhibit faster tumor rejection kinetics, earlier intratumoral accumulation, and signs of activation. Metabolic profiling also indicates that TRuC-T cells have lower glycolytic activity and higher mitochondrial metabolism than CAR-T cells. These findings highlight TRuC-T cells as a promising cell therapy for MSLN-expressing cancers.
Article
Oncology
Konstantinos Lontos, Yiyang Wang, Supriya K. Joshi, Andrew T. Frisch, McLane J. Watson, Alok Kumar, Ashley Menk, Yupeng Wang, Rachel Cumberland, Jason Lohmueller, Esteban Carrizosa, Benjamin Boyerinas, Greg M. Delgoffe
Summary: This study demonstrates that an engineered version of the inhibitory transcription factor PGC-1 alpha can metabolically reprogram human CAR-T cells, resulting in improved in vivo efficacy for the treatment of solid tumors. In contrast, a truncated version of PGC-1 alpha, NT-PGC-1 alpha, did not improve the in vivo outcomes.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2023)
Article
Oncology
Ryan C. Augustin, Ziyu Huang, Fei Ding, Shuyan Zhai, Jennifer McArdle, Anthony Santisi, Michael Davis, Cindy Sander, Diwakar Davar, John M. Kirkwood, Greg M. Delgoffe, Allison Betof Warner, Yana G. Najjar
Summary: In this study, it was found that metformin treatment in diabetic melanoma patients is associated with lower recurrence rates, higher survival rates, and reduced incidence of brain metastases.
FRONTIERS IN ONCOLOGY
(2023)
Article
Medicine, Research & Experimental
Frank P. Vendetti, Pinakin Pandya, David A. Clump, Sandra Schamus-Haynes, Meysam Tavakoli, Maria diMayorca, Naveed M. Islam, Jina Chang, Greg M. Delgoffe, Jan H. Beumer, Christopher J. Bakkenist
Summary: Inhibitors of the ATR kinase can enhance the killing of tumor cells by DNA replication fork-targeting chemotherapies but also affect rapidly proliferating immune cells. Combining ATR inhibitor and radiotherapy can stimulate CD8+ T cell-dependent antitumor responses. The optimal schedule of ATR inhibitor and radiotherapy is determined by the duration of ATR inhibitor treatment, which affects the expansion of tumor antigen-specific CD8+ T cells.
Article
Immunology
Kristin Depeaux, Dayana B. Rivadeneira, Konstantinos Lontos, Victoria G. Dean, William G. Gunn, McLane J. Watson, Tianhong Yao, Drew Wilfahrt, Cynthia Hinck, Lukasz Wieteska, Stephen H. Thorne, Andrew P. Hinck, Greg M. Delgoffe
Summary: Oncolytic viruses can induce tumor lysis and activate the tumor microenvironment, but they do not relieve immunosuppressive signals. Engineering oncolytic vaccinia virus to express a potent TGF beta R inhibitor can neutralize TGF beta locally, increase fragility of Treg cells, and achieve a superior therapeutic response.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Hematology
Emily Landy, Jemy Varghese, Vinh Dang, Andrea Szymczak-Workman, Lawrence P. Kane, Scott W. Canna
Summary: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes. Understanding the synergistic effect of susceptibility factors can reveal key pathomechanisms in the activation of CD8 T cells.
Article
Gastroenterology & Hepatology
Ansen H. P. Burr, Junyi Ji, Kadir Ozler, Heather L. Mentrup, Onur Eskiocak, Brian Yueh, Rachel Cumberland, Ashley V. Menk, Natalie Rittenhouse, Chris W. Marshall, Pailin Chiaranunt, Xiaoyi Zhang, Lauren Mullinax, Abigail Overacre-Delgoffe, Vaughn S. Cooper, Amanda C. Poholek, Greg M. Delgoffe, Kevin P. Mollen, Semir Beyaz, Timothy W. Hand
Summary: This study revealed the direct impact of high-sugar diet on the function of colonic stem cells and transit-amplifying cells using 3-dimensional colonoids and a mouse model of colon damage and repair. The findings showed that high-sugar conditions restrict colonoid development, reduce the expression of proliferative genes, ATP levels, and lead to pyruvate accumulation. Treatment with dichloroacetate restored colonoid growth. Moreover, a high-sugar diet combined with dextran sodium sulfate treatment resulted in severe irreparable colon damage. ISC gene expression was reduced, proliferative potential was impeded, and glycolytic potential was increased without a corresponding increase in aerobic respiration.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2023)
Article
Microbiology
Grace P. Carreno-Florez, Brian R. Kocak, Matthew R. Hendricks, Jeffrey A. Melvin, Katrina B. Mar, Jessica Kosanovich, Rachel L. Cumberland, Greg M. Delgoffe, Sruti Shiva, Kerry M. Empey, John W. Schoggins, Jennifer M. Bomberger
Summary: Viral infections can make the host susceptible to secondary bacterial infections, and this study identified specific interferon-stimulated genes (ISGs) that promote Pseudomonas aeruginosa infection. The mechanism of action was also investigated, revealing the role of hexokinase 2 (HK2) in mediating metabolic changes and lactate secretion to enhance bacterial infection. These findings improve our understanding of how the host immune response can lead to viral-bacterial co-infection.
Meeting Abstract
Oncology
A. Yassin-Kassab, R. A. Harbison, N. Wang, M. Burns, G. Delgoffe, U. Duvvuri
EUROPEAN JOURNAL OF CANCER
(2022)
Meeting Abstract
Oncology
Nicole N. Scheff, Marci Lee Nilsen, Jinhong Li, Alexandria L. Harris, Andrew Swartz, Ronan Wenhan Hsieh, Jennifer Lynn Anderson, Robert L. Ferris, Ashley Menk, Greg M. Delgoffe, Dan Paul Zandberg
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Review
Medicine, Research & Experimental
McLane J. Watson, Greg M. Delgoffe
Summary: The tumor microenvironment depletes essential nutrients and produces toxic metabolites that shape immune cell function and impact cancer immunotherapy.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
