Immunology

Discovery of a Potent and Selective Inhibitor of Human NLRP3 with a Novel Binding Modality and Mechanism of Action

1. Kevin Wilhelmsen
2. Aditi Deshpande
3. Sarah Tronnes
4. Maitriyee Mahanta
5. Matthew Banicki
6. Mary Cochran
7. Samantha Cowdin
8. Kristen Fortney
9. George Hartman
10. Robert Hughes
11. Rusty Montgomery
12. Claudia Portillo
13. Paul Rubin
14. Yan Wang
15. Shijun Yan
16. Barry A Morgan
17. Assem Duisembekova
18. Romane Riou
19. Michael Marleaux
20. Inga V. Hochheiser
21. Hannes Buthmann
22. Dominic Ferber
23. Wei Wang
24. Melanie Cranston
25. Chloe M. McKee
26. Thea Mawhinney
27. Emma McKay
28. Bénédicte F. Py
29. Matthias Geyer
30. Rebecca C. Coll

Reviewed by preLights

SIV-specific neutralizing antibody induction following selection of a PI3K drive-attenuated nef variant

1. Hiroyuki Yamamoto
2. Tetsuro Matano

• Curated by eLife

  eLife Assessment

  Yamamoto and Matano provide convincing evidence that a G63E/R CD8+ T-cell escape mutation in the accessory viral protein Nef promote the induction of neutralizing antibody (nAb) responses in rhesus macaques infected with SIVmac239, which is usually largely resistant to neutralization. Functional analyses support that this mutation specifically impairs Nef`s ability to stimulate PI3K/Akt/mTORC2 signalling. This important study suggests that the accessory viral protein Nef impairs B cell function and effective humoral immune responses and is of interest for researchers and physicians interested in HIV/AIDS and vaccine development.

Reviewed by eLife

Genome Restructuring around Innate Immune Genes in Monocytes in Alcohol-associated Hepatitis

1. Adam Kim
2. Megan R McMullen
3. Annette Bellar
4. David Streem
5. Jaividhya Dasarathy
6. Nicole Welch
7. Srinivasan Dasarathy

• Curated by eLife

  eLife Assessment

  The manuscript addresses the 3D chromatin architecture in monocytes from patients with alcohol-associated hepatitis and its relationship to enhanced transcription of innate immune genes. While the concept and methodological approach are appealing, the evidence is incomplete as a result of insufficient sample sizes as well as other significant analytical concerns.

Reviewed by eLife

DGKα and ζ Deficiency Causes Regulatory T-Cell Dysregulation, Destabilization, and Conversion to Pathogenic T-Follicular Helper Cells to Trigger IgG1-Predominant Autoimmunity

1. Lei Li
2. Hongxiang Huang
3. Hongxia Wang
4. Yun Pan
5. Huishan Tao
6. Shimeng Zhang
7. Peer W.F. Karmaus
8. Michael B. Fessler
9. John W. Sleasman
10. Xiao-Ping Zhong

• Curated by eLife

  eLife Assessment

  This study presents a valuable finding on the signaling mechanisms underlying Treg cell homeostasis by identifying the simultaneous requirement of diacylglycerol (DAG) kinases (DGK) alpha and zeta for Foxp3+ Treg cell function and follicular responses, with implications for the pathogenesis of some autoimmune diseases. Whereas data based on the characterization of double knock-out mice (for DGK alpha and zeta) is solid, showing the emergence of autoimmune manifestations, the study has gaps in its experimental approaches since it is not clear what can be attributed to the simultaneous DKGα and ζ deficiency, versus the individual deficiency of either one. Experiments on the pathogenic potential of the DKO Tregs in the absence of other T-cells were not presented and results on the role of CD25 downregulation and CD28-independent activation of Treg cells were not properly discussed. Nonetheless, the reported data would be of interest to immunologists working on T-cell intracellular signaling and autoimmunity.

Reviewed by eLife

Unraveling the power of NAP-CNB’s machine learning-enhanced tumor neoantigen prediction

1. Almudena Mendez-Perez
2. Andres M Acosta-Moreno
3. Carlos Wert-Carvajal
4. Pilar Ballesteros-Cuartero
5. Ruben Sánchez-García
6. Jose R Macias
7. Rebeca Sanz-Pamplona
8. Ramon Alemany
9. Carlos Oscar Sorzano
10. Arrate Munoz-Barrutia
11. Esteban Veiga

• Curated by eLife

  eLife Assessment

  Veiga et al demonstrate the importance of incorporating RNAseq and machine learning approaches for neoantigen prediction. The evidence is convincing, and these findings contribute important information towards the selection of neoantigens for personalized antitumor vaccination.

Reviewed by eLife

Expression of a single inhibitory member of the Ly49 receptor family is sufficient to license NK cells for effector functions

1. Sytse J Piersma
2. Shasha Li
3. Pamela Wong
4. Michael D Bern
5. Jennifer Poursine-Laurent
6. Liping Yang
7. Diana L Beckman
8. Bijal A Parikh
9. Wayne M Yokoyama

• Curated by eLife

  eLife Assessment

  This study on mouse Ly49 receptors expressed on natural killer (NK) cells shows that Ly49A, in the presence of the corresponding MHC Class I allele, can lead to NK cell licensing, thereby providing valuable insights into the mechanisms of NK cell modulation by Ly49 receptors. The work may have significant implications for studies of human Killer-cell immunoglobulin-like receptors (KIR) expressing and other NK cells. Overall, the study was well-developed with convincing evidence.

Reviewed by eLife

Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis

1. Alexander J Knights
2. Easton C Farrell
3. Olivia M Ellis
4. Michelle J Song
5. C Thomas Appleton
6. Tristan Maerz

• Curated by eLife

  eLife assessment

  This study provides useful information by identifying the cell type (macrophages) in synovial tissues involved in the pathogenesis of post-traumatic osteoarthritis (OA) and clarifying distinct transcriptomic signatures that may be a good therapeutic target for OA. However, the analysis performed so far is incomplete, with a main weakness being the lack of data to confirm the authors' speculation about the underlying mechanisms.

Reviewed by eLife

Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistance

1. Marianna Ponzo
2. Lorenzo Drufuca
3. Chiara Buracchi
4. Marco M. Sindoni
5. Silvia Nucera
6. Cristina Bugarin
7. Ramona Bason
8. Grazisa Rossetti
9. Raoul Bonnal
10. Cristian Meli
11. Benedetta Rambaldi
12. Federico Lussana
13. Silvia Ferrari
14. Alex Moretti
15. Giulia Risca
16. Christian Pellegrino
17. Markus G. Manz
18. Stefania Galimberti
19. Alessandro Rambaldi
20. Giuseppe Gaipa
21. Andrea Biondi
22. Massimiliano Pagani
23. Chiara F. Magnani

Reviewed by PREreview

T3SS translocon induces pyroptosis by direct interaction with NLRC4/NAIP inflammasome

1. Yan Zhao
2. Hanshuo Zhu
3. Jinqian Li
4. Hang Xu
5. Li Sun

• Curated by eLife

  eLife Assessment

  This important study shows that Type 3 secretion translocons in Edwardsiella tarda and other bacteria activate the NAIP-NLRC4 inflammasome. The data from cellular and biochemical experiments showing that EseB is required for activation of the NLRC4 inflammasome are convincing. This paper is broadly relevant to those investigating host-pathogen interactions in diverse organisms.

Reviewed by eLife

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism

1. Wesley H. Godfrey
2. Judy J. Lee
3. Shruthi Shanmukha
4. Kaho Cho
5. Xiaojing Deng
6. Chandra Shekar R. Ambati
7. Vasanta Putluri
8. Abu Hena Mostafa Kamal
9. Paul M. Kim
10. Nagireddy Putluri
11. Michael D. Kornberg

• Curated by eLife

  eLife Assessment

  The results highlight an important physiological function of PGAM in the differentiation and suppressive activity of Treg cells by regulating serine synthesis. This role is proposed to intersect with glycolysis and one-carbon metabolism. Although the study's conclusion is supported by solid evidence from in-vitro cellular and in-vivo mouse models, there are some weaknesses and the reviewers suggested ways to improve the manuscript.

Reviewed by eLife