bims-nastce 2022-04-17 papers

EMBO Rep. 2022 Apr 11. e54271

Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease.

Chun-Yi Ng, Khang Leng Lee, Mark Dhinesh Muthiah, Kan Xing Wu, Florence Wen Jing Chioh, Konstanze Tan, Gwyneth Shook Ting Soon, Asim Shabbir, Wai Mun Loo, Zun Siong Low, Qingfeng Chen, Nguan Soon Tan, Huck Hui Ng, Yock Young Dan, Christine Cheung.

The top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular complications. However, mechanisms of NAFLD-associated vasculopathy remain understudied. Here, we show that blood outgrowth endothelial cells (BOECs) from NAFLD subjects exhibit global transcriptional upregulation of chemokines and human leukocyte antigens. In mouse models of diet-induced NAFLD, we confirm heightened endothelial expressions of CXCL12 in the aortas and the liver vasculatures, and increased retention of infiltrated leukocytes within the vessel walls. To elucidate endothelial-immune crosstalk, we performed immunoprofiling by single-cell analysis, uncovering T cell intensification in NAFLD patients. Functionally, treatment with a CXCL12-neutralizing antibody is effective at moderating the enhanced chemotactic effect of NAFLD BOECs in recruiting CD8+ T lymphocytes. Interference with the CXCL12-CXCR4 axis using a CXCR4 antagonist also averts the impact of immune cell transendothelial migration and restores endothelial barrier integrity. Clinically, we detect threefold more circulating damaged endothelial cells in NAFLD patients than in healthy controls. Our work provides insight into the modulation of interactions with effector immune cells to mitigate endothelial injury in NAFLD.

Keywords: chemokine ligand-receptor interaction; circulating endothelial cells; endothelial dysfunction; immunoprofiling; transcriptomics

DOI: https://doi.org/10.15252/embr.202154271

Science. 2022 Apr 15. 376(6590): 243-244

Regulatory CD8+ T cells suppress disease.

Anaïs Levescot, Nadine Cerf-Bensussan.

A subset of CD8+ T cells regulate chronic inflammation by killing pathogenic CD4+ T cells.

DOI: https://doi.org/10.1126/science.abp8243

J Immunol. 2022 Apr 13. pii: ji2100313. [Epub ahead of print]

Adipocyte CD1d Gene Transfer Induces T Cell Expansion and Adipocyte Inflammation in CD1d Knockout Mice.

Run Xiao, Anthony G Mansour, Wei Huang, Quais N Hassan, Ryan K Wilkins, Suraj V Komatineni, Rhiannon Bates, Seemaab Ali, Logan A Chrislip, Nicholas J Queen, Shoubao Ma, Jianhua Yu, Matthew R Lordo, Bethany L Mundy-Bosse, Michael A Caligiuri, Lei Cao.

CD1d, a lipid Ag-presenting molecule for invariant NKT (iNKT) cells, is abundantly expressed on adipocytes and regulates adipose homeostasis through iNKT cells. CD1d gene expression was restored in visceral adipose tissue adipocytes of CD1d knockout (KO) mice to investigate the interactions between adipocytes and immune cells within adipose tissue. We developed an adipocyte-specific targeting recombinant adeno-associated viral vector, with minimal off-target transgene expression in the liver, to rescue CD1d gene expression in visceral adipose tissue adipocytes of CD1d KO mice, followed by assessment of immune cell alternations in adipose tissue and elucidation of the underlying mechanisms of alteration. We report that adeno-associated virus-mediated gene transfer of CD1d to adipocytes in CD1d KO mice fails to rescue iNKT cells but leads to massive and selective expansion of T cells within adipose tissue, particularly CD8+ T effector cells, that is associated with adipocyte NLRP3 inflammasome activation, dysregulation of adipocyte functional genes, and upregulation of apoptotic pathway proteins. An NLRP3 inhibitor has no effect on T cell phenotypes whereas depletion of CD8+ T cells significantly attenuates inflammasome activation and abolishes the dysregulation of adipocyte functional genes induced by adipocyte CD1d. In contrast, adipocyte overexpression of CD1d fails to induce T cell activation in wild-type mice or in invariant TCR α-chain Jα18 KO mice that have a normal lymphocyte repertoire except for iNKT cells. Our studies uncover an adipocyte CD1d → CD8+ T cell → adipocyte inflammasome cascade, in which CD8+ T cells function as a key mediator of adipocyte inflammation likely induced by an allogeneic response against the CD1d molecule.

DOI: https://doi.org/10.4049/jimmunol.2100313

Sci Transl Med. 2022 Apr 13. 14(640): eabl6058

Tissue-resident memory CD8+ T cells cooperate with CD4+ T cells to drive compartmentalized immunopathology in the CNS.

In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8+ TRM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8+ TRM. Subsequently, CD8+ TRM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8+ T cells. However, in the absence of CD4+ T cells, TCF-1+ CD8+ TRM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8+ T cells expressing TCF-1 that predominantly exhibited a TRM-like phenotype. Together, our study provides evidence for CD8+ TRM-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.

DOI: https://doi.org/10.1126/scitranslmed.abl6058

Sci Transl Med. 2022 Apr 13. 14(640): eabl6157

Tissue-resident CD8+ T cells drive compartmentalized and chronic autoimmune damage against CNS neurons.

David Frieser, Aurora Pignata, Leila Khajavi, Danielle Shlesinger, Carmen Gonzalez-Fierro, Xuan-Hung Nguyen, Alexander Yermanos, Doron Merkler, Romana Höftberger, Virginie Desestret, Katharina M Mair, Jan Bauer, Frederick Masson, Roland S Liblau.

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (TRM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8+ T cells exhibit a TRM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8+ T cells behind the blood-brain barrier adopt a characteristic TRM differentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8+ T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8+ T cells. Consistently, a large fraction of autoreactive tissue-resident CD8+ T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8+ T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4+ T cells. Collectively, our results point to tissue-resident CD8+ T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.

DOI: https://doi.org/10.1126/scitranslmed.abl6157

Science. 2022 Apr 15. 376(6590): eabf8271

Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.

Bridget S Gosis, Shogo Wada, Chelsea Thorsheim, Kristina Li, Sunhee Jung, Joshua H Rhoades, Yifan Yang, Jeffrey Brandimarto, Li Li, Kahealani Uehara, Cholsoon Jang, Matthew Lanza, Nathan B Sanford, Marc R Bornstein, Sunhye Jeong, Paul M Titchenell, Sudha B Biddinger, Zoltan Arany.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element-binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.

DOI: https://doi.org/10.1126/science.abf8271

Science. 2022 Apr 15. 376(6590): 247-248

Complex regulation of fatty liver disease.

Henry N Ginsberg, Arya Mani.

Hepatic lipogenesis is fine-tuned by mechanistic target of rapamycin (mTOR) signaling.

DOI: https://doi.org/10.1126/science.abp8276