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In this issue of JEM, Reijers et al. demonstrate that pre- and post-treatment IFNγ-related gene expression scores are promising markers for choosing neoadjuvant immunotherapy for stage III melanoma.

A genome-wide CRISPR/Cas9 knockout screen uncovered novel mechanisms of adaptive resistance to pharmacologic inhibition of SHP2.

CRISPR/Cas9 genome editing techniques have the potential to treat previously untreatable inherited genetic disorders of vision by correcting mutations that cause these afflictions. Using a prime editor, Qin et al. restored visual functions in a mouse model (rd10) of retinitis pigmentosa.

Milky spots of the omentum enable lymphocyte access to the peritoneal cavity. In this issue of JEM, Yoshihara and Okabe demonstrate how secretion of retinoic acid by fibroblastic reticular cells allows lymphocyte entry into milky spots and the peritoneal cavity.

In this issue of JEM, Qiu et al. show that retinoic acid signaling during priming in the mesenteric lymph node licenses CD8+ T cells to develop into small intestinal tissue-resident memory cells, a finding that provides key insights into tissue-specific vaccination strategies.

Brief Definitive Reports

MyD88- and IRAK-4–deficient patients have a higher risk of hypoxemic COVID-19 pneumonia than individuals of similar age in the general population, due to impaired TLR7-dependent type I IFN production.


In the DONIMI trial, a baseline IFN-γ signature enables prospective selection of patients who can benefit from anti-PD-1 monotherapy. In contrast to results of our murine melanoma model, domatinostat (a class I HDAC inhibitor) does not add benefit to neoadjuvant anti-PD-1 ± anti-CTLA-4 in patients.

In Special Collection: JEM Cancer Collection 2023

Genome-wide and focused CRISPR/Cas9 screens for SHP2i resistance in multiple cancer lines identified novel in vitro and in vivo resistance genes. Deletion of these genes results in ERK activation and cross-resistance to FLT3-ITD/BCR-ABL inhibition in FLT3-ITD or BCR-ABL–driven AML lines.

In Special Collection: Neuroscience Collection 2023

Qin and colleagues develop a genome-editing tool characterized by the versatility of prime editors and unconstrained PAM requirement of SpRY. In vivo gene correction is successfully implemented in the mouse model of Pde6b-associated retinitis pigmentosa, leading to substantial functional rescue of vision.

This study unveils a subset of fibroblastic reticular cells that play an essential role in the formation of milky spots of visceral adipose tissue omentum by regulating lymphocyte recruitment.

In Special Collection: JEM Immunology Collection 2023

Qiu et al. demonstrate that retinoic acid signaling during T cell priming in the mesenteric lymph nodes licenses the differentiation of CD103+ CD8 tissue-resident memory T cells after entry into the small intestine, which may improve rational vaccine design.

Mehul Sharma,Daniel Leung,Mana Momenilandi,Lauren C.W. Jones,Lucia Pacillo,Alyssa E. James,Jill R. Murrell,Selket Delafontaine,Jesmeen Maimaris,Maryam Vaseghi-Shanjani,Kate L. Del Bel,Henry Y. Lu,Gilbert T. Chua,Silvia Di Cesare,Oriol Fornes,Zhongyi Liu,Gigliola Di Matteo,Maggie P. Fu,Donato Amodio,Issan Yee San Tam,Gavin Shueng Wai Chan,Ashish A. Sharma,Joshua Dalmann,Robin van der Lee,Géraldine Blanchard-Rohner,Susan Lin,Quentin Philippot,Phillip A. Richmond,Jessica J. Lee,Allison Matthews,Michael Seear,Alexandra K. Turvey,Rachael L. Philips,Terri F. Brown-Whitehorn,Christopher J. Gray,Kosuke Izumi,James R. Treat,Kathleen H. Wood,Justin Lack,Asya Khleborodova,Julie E. Niemela,Xingtian Yang,Rui Liang,Lin Kui,Christina Sze Man Wong,Grace Wing Kit Poon,Alexander Hoischen,Caspar I. van der Made,Jing Yang,Koon Wing Chan,Jaime Sou Da Rosa Duque,Pamela Pui Wah Lee,Marco Hok Kung Ho,Brian Hon Yin Chung,Huong Thi Minh Le,Wanling Yang,Pejman Rohani,Ali Fouladvand,Hassan Rokni-Zadeh,Majid Changi-Ashtiani,Mohammad Miryounesi,Anne Puel,Mohammad Shahrooei,Andrea Finocchi,Paolo Rossi,Beatrice Rivalta,Cristina Cifaldi,Antonio Novelli,Chiara Passarelli,Stefania Arasi,Dominique Bullens,Kate Sauer,Tania Claeys,Catherine M. Biggs,Emma C. Morris,Sergio D. Rosenzweig,John J. O’Shea,Wyeth W. Wasserman,H. Melanie Bedford,Clara D.M. van Karnebeek,Paolo Palma,Siobhan O. Burns,Isabelle Meyts,Jean-Laurent Casanova,Jonathan J. Lyons,Nima Parvaneh,Anh Thi Van Nguyen,Caterina Cancrini,Jennifer Heimall,Hanan Ahmed,Margaret L. McKinnon,Yu Lung Lau,Vivien Béziat,Stuart E. Turvey

Sharma et al. define a new primary atopic disorder caused by heterozygous gain-of-function variants in STAT6. This results in severe, early-onset allergies, and is seen in 16 patients from 10 families. Anti–IL-4Rα antibody and JAK inhibitor treatment were highly effective.

Age-associated B cells are heterogeneous with respect to expression of memory and plasmablast markers. Unlike resting memory, ABCs are chronically activated, with the capacity for self-renewal or differentiation. Depletion of CD11c+ ABCs improved renal disease in the MRL/lpr lupus model.

Follicular T helper (Tfh) cells coordinate optimal germinal center responses, but abnormal Tfh cell function contributes to autoantibody-dependent autoimmunity. Seth et al. demonstrate that AP-1–independent NFAT gene expression, typically associated with hyporesponsive T cells, is required for Tfh cell maintenance and is a therapeutic target in murine lupus.

A transcriptional rheostat orchestrated by RELA is found to control the expression of type I/III interferon in T cells. Unlocking IFN-I/III expression in T cells confers self-defense against HIV infection and increases the antitumor activity of CAR T cells.

Metastatic cancer cells thrive in secondary organs by producing PTN and activating the NF-κB pathway. This leads to increased cytokine production, neutrophil recruitment, and T cell dysfunction. Targeting PTN presents a promising addition to the current regimen for treating metastatic TNBC.

Intercellular communications across different layers of the intestine remain poorly understood. Here, Wang et al. show the heterogeneity and developmental trajectories of intestinal intraepithelial lymphocytes, lamina propria lymphocytes, and intestinal epithelial cells, and the cell type-specific homeostatic interactomes in response to a Western diet.

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