Ma et al. report that the alternative complement pathway, via adipsin and C3aR1, regulate adipocyte metabolism in a sex-dependent fashion. Image credit: ALIOUI MA/Shutterstock.
Memory T cells are conventionally associated with durable recall responses. In our longitudinal analyses of CD4+ T cell responses to the yellow fever virus (YFV) vaccine by peptide-MHC tetramers, we unexpectedly found CD45RO-CCR7+ virus-specific CD4+ T cells that expanded shortly after vaccination and persisted months to years after immunization. Further phenotypic analyses revealed the presence of stem-cell memory T cells (TSCM) within this subset. In addition, post-vaccine T cells lacking known memory markers and functionally resembling genuine naïve T cells were identified, referred to herein as marker-negative T cells (TMN). Single-cell TCR sequencing detected expanded clonotypes within the TMN subset and identified TMN TCRs shared with memory and effector T cells. Longitudinal tracking of YFV-specific responses over subsequent years revealed superior stability of TMN cells, which correlated with the longevity of the overall tetramer+ population. These findings uncovered additional complexity within the post-immune T cell compartment and implicate TMN cells in durable immune responses.
Yi-Gen Pan, Laurent Bartolo, Ruozhang Xu, Bijal V. Patel, Veronika I. Zarnitsyna, Laura F. Su
Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here we show that ferroptosis negative regulation (FNR) signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/4EBP1 signaling promoted SLC7A11 protein synthesis, leading to ferroptosis inhibition in MEK inhibitor resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR-4EBP1 activity to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
Jiaxin Yin, Jianfeng Chen, Jing Han Hong, Yulin Huang, Rong Xiao, Shini Liu, Peng Deng, Yichen Sun, Kelila Xin Ye Chai, Xian Zeng, Jason Yongsheng Chan, Peiyong Guan, Yali Wang, Peili Wang, Chongjie Tong, Qiang Yu, Xiaojun Xia, Choon Kiat Ong, Bin Tean Teh, Ying Xiong, Jing Tan
Sleep disturbance usually accompanies anxiety disorders and exacerbates their incidence rates. The precise circuit mechanisms remain poorly understood. Here, we found that glutamatergic neurons in the posteroventral medial amygdala (MePVGlu) are involved in arousal and anxiety-like behaviors. Excitation of MePVGlu neurons not only promoted wakefulness but also increased anxiety-like behaviors. Different projections of MePVGlu neurons played various roles in regulating anxiety-like behaviors and sleep-wakefulness. MePVGlu neurons promoted wakefulness through the MePVGlu-posteromedial cortical amygdaloid area (PMCo) pathway and the MePVGlu-bed nucleus of the stria terminals (BNST) pathway. In contrast, MePVGlu neurons increased anxiety-like behaviors through the MePVGlu-ventromedial hypothalamus (VMH) pathway. Chronic sleep disturbance increased anxiety levels and reduced reparative sleep, accompanied by the enhanced excitability of MePVGlu-PMCo and MePVGlu-VMH circuits but suppressed responses of glutamatergic neurons in the BNST. Inhibition of the MePVGlu neurons could rescue chronic sleep deprivation-induced phenotypes. Our findings provide important circuit mechanisms for chronic sleep disturbance-induced hyperarousal response and obsessive anxiety-like behavior, and are expected to provide a promising strategy for treating sleep-related psychiatric disorders and insomnia.
Ying Li, Yuchen Deng, Yifei Zhang, Dan Xu, Xuefen Zhang, Yue Li, Yidan Li, Ming Chen, Yuxin Wang, Jiyan Zhang, Like Wang, Yufeng Cang, Peng Cao, Linlin Bi, Haibo Xu
Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 autoimmune subjects, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell–depleted multiple sclerosis (MS) subjects were associated with higher CD8 T cell responses. By contrast, subjects taking mycophenolate mofetil exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low IgG anti-spike response included B cell depletion within the last year, fingolimod, and combination treatment with mycophenolate mofetil (MMF) and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine, is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of pre-existing anti-type I interferon antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2–related deaths suggest that T cell immunity contributes to protection in autoimmune disease.
Erik Anderson, Michael Powell, Emily Yang, Ananya Kar, Tung Ming Leung, Cristina Sison, Rebecca Steinberg, Raven Mims, Ananya Choudhury, Carlo Espinosa, Joshua Zelmanovich, Nkemakonam C. Okoye, Eun Jung Choi, Galina Marder, Sonali Narain, Peter K. Gregersen, Meggan Mackay, Betty Diamond, Todd Levy, Theodoros P. Zanos, Arezou Khosroshahi, Ignacio Sanz, Eline T. Luning Prak, Amit Bar-Or, Joan Merrill, Cristina Arriens, Gabriel Pardo, Joel Guthridge, Judith James, Aimee Payne, Paul J. Utz, Jeremy M. Boss, Cynthia Aranow, Anne Davidson
The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response, and how incorporation of human-specific physiological nutrient media might help to identify compounds whose efficacy could be impacted in humans.
Vipin Rawat, Patrick DeLear, Prarthana Prashanth, Mete Emir Ozgurses, Anteneh Tebeje, Philippa A. Burns, Kelly O. Conger, Christopher Solís, Yasir Hasnain, Anna Novikova, Jennifer E. Endress, Paloma González-Sánchez, Wentao Dong, Greg Stephanopoulos, Gina M. DeNicola, Isaac Harris, David Sept, Frank M. Mason, Jonathan L. Coloff