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Monday February 10, 2020

The results are in!

We are very excited to showcase Immunology & Cell Biology's Top Cited Publications for Jan 2018 - Dec 2019.

Congratulations to the authors of the following papers:

Immune checkpoint inhibitors in cancer therapy: a focus on T‐regulatory cells

Varun Sasidharan Nair, Eyad Elkord.

Regulatory T cells (Tregs) play essential roles in immune homeostasis; however, their role in tumor microenvironment (TME) is not completely evident. Several studies reported that infiltration of Tregs into various tumor tissues promotes tumor progression by limiting antitumor immunity and supporting tumor immune evasion. Furthermore, in TME, Tregs include heterogeneous subsets of cells expressing different immunosuppressive molecules favoring tumor progression. For an effective cancer therapy, it is critical to understand the Treg heterogeneity and biology in the TME. Recent studies have shown that immune checkpoint molecules promote cancer progression through various antitumor inhibitory mechanisms. Recent advances in cancer immunotherapy have shown the promising potentials of immune checkpoint inhibitors (ICIs) in inducing antitumor immune responses and clinical benefits in patients with cancer at late stages. Most studies revealed the effect of ICIs on T effector cells, and little is known about their effect on Tregs. In this review, we highlight the effects of the ICIs, including anti‐CTLA‐4, anti‐PD‐1/PD‐L1, anti‐LAG‐3, anti‐TIM‐3, and anti‐TIGIT, on tumor‐infiltrating and peripheral Tregs to elicit effector T‐cell functions against tumors. Additionally, we discuss how ICIs may target Tregs for cancer immunotherapy.

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Human blood MAIT cell subsets defined using MR1 tetramers

Nicholas A Gherardin, Michael NT Souter, Hui‐Fern Koay, Kirstie M Mangas, Torsten Seemann, Timothy P Stinear, Sidonia BG Eckle, Stuart P Berzins, Yves d'Udekem, Igor E Konstantinov, David P Fairlie, David S Ritchie, Paul J Neeson, Daniel G Pellicci, Adam P Uldrich, James McCluskey, Dale I Godfrey.

Mucosal‐associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non‐lineage‐specific (surrogate) markers such as anti‐TRAV1‐2, CD161, IL‐18Rα and CD26. The development of MR1‐Ag tetramers now permits the specific identification of MAIT cells based on T‐cell receptor specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4+ fraction. Moreover, while all MAIT cell subsets produced comparable levels of IFNγ, TNF and IL‐17A, the CD4+ population produced more IL‐2 than the other subsets. In a human ontogeny study, we show that the frequencies of most MR1 tetramer+ MAIT cells, with the exception of CD4+ MAIT cells, increased from birth to about 25 years of age and declined thereafter. We also demonstrate a positive association between the frequency of MAIT cells and other unconventional T cells including Natural Killer T (NKT) cells and Vδ2+ γδ T cells. Accordingly, this study demonstrates that MAIT cells are phenotypically and functionally diverse, that surrogate markers may not reliably identify all of these cells, and that their numbers are regulated in an age‐dependent manner and correlate with NKT and Vδ2+ γδ T cells.

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The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition

Maureen Bardet, Adeline Unterreiner, Claire Malinverni, Frédérique Lafossas, Corinne Vedrine, Danielle Boesch, Yeter Kolb, Daniel Kaiser, Anton Glück, Martin A Schneider, Andreas Katopodis, Martin Renatus, Oliver Simic, Achim Schlapbach, Jean Quancard, Catherine H Régnier, Guido Bold, Carole Pissot‐Soldermann, José M Carballido, Jiri Kovarik, Thomas Calzascia, Frédéric Bornancin.

Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T‐cell activation and fate after engagement of the T‐cell receptor pathway. We show that MLT‐827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T‐cell activation, in contrast to the pan‐protein kinase C inhibitor AEB071. However, MLT‐827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL‐2 production as well as reduced expression of the IL‐2 receptor alpha subunit (CD25), resulting from defective canonical NF‐κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT‐827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T‐cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT1 paracaspase activity integrates several T‐cell activation pathways and indirectly controls gamma‐chain receptor dependent survival, to impact on T‐cell expansion.

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Mendelian susceptibility to mycobacterial disease: 2014–2018 update

Jérémie Rosain, Xiao‐Fei Kong, Ruben Martinez‐Barricarte, Carmen Oleaga‐Quintas, Noé Ramirez‐Alejo, Janet Markle, Satoshi Okada, Stéphanie Boisson‐Dupuis, Jean‐Laurent Casanova, Jacinta Bustamante.

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN‐γ immunity. Since 1996, disease‐causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase‐like 2 A deficiency, (2) TYK2‐deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN‐γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.

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MAIT cells and viruses

James E Ussher, Christian B Willberg, Paul Klenerman

Mucosal associated invariant T cells (MAIT cells) bear a T cell receptor (TCR) that specifically targets microbially derived metabolites. Functionally, they respond to bacteria and yeasts, which possess the riboflavin pathway, essential for production of such metabolites and which are presented on MR1. Viruses cannot generate these ligands, so a priori, they should not be recognized by MAIT cells and indeed this is true when considering recognition through the TCR. However, MAIT cells are distinctive in another respect, since they respond quite sensitively to non‐TCR signals, especially in the form of inflammatory cytokines. Thus, a number of groups have shown that virus infection can be “sensed” by MAIT cells and a functional response invoked. Since MAIT cells are abundant in humans, especially in tissues such as the liver, the question has arisen as to whether this TCR‐independent MAIT cell triggering by viruses plays any role in vivo. In this review, we will discuss the evidence for this phenomenon and some common features which emerge across different recent studies in this area.

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