Contents | Science Immunology 7, 74

ONLINE COVER Exclusion of CD45 from a CAR-T Synapse. This month’s cover features a confocal microscopy image in which a human T cell expressing a CD19-targeting chimeric antigen receptor (CAR), stained in red, has formed an immunological synapse with a human Raji B cell lymphoma cell (blue). CD45 (green), a bulky tyrosine phosphatase enzyme that can inhibit CAR-T activation, is effectively excluded from the central portion of this synapse. Xiao et al. developed a size-exclusion model to explain how the relative sizes of the CAR construct and the CD45 isoform on a CAR-T cell and the target antigen on a tumor cell calibrate CD45’s dampening of antigen-triggered CAR-T activation at the synapse.

Credit: Xiaolei Su/Yale University

Science Immunology

Volume 7|
Issue 74|
Aug 2022

Credit: Xiaolei Su/Yale University

Editorial

Operation Nasal Vaccine—Lightning speed to counter COVID-19

- Eric J. Topol
- Akiko Iwasaki
19 Aug 2022
Free

Given the poor ability of intramuscular mRNA COVID-19 vaccines to induce robust immunity in the respiratory mucosa, a push for a nasal vaccine strategy is needed.

Research Articles

Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells

- B. Rhodes Ford
- Paolo D. A. Vignali
- Natalie L. Rittenhouse
- Nicole E. Scharping
- Ronal Peralta
- Konstantinos Lontos
- Andrew T. Frisch
- Greg M. Delgoffe
- Amanda C. Poholek
05 Aug 2022
NO ACCESS

Insufficient costimulation and hypoxia exposure induce epigenetic remodeling enforcing dysfunction in exhausted T cells.

Abstract

Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms ...

PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes

- Cristina C. Clement
- Jaspreet Osan
- Aitziber Buque
- Padma P. Nanaware
- Yoke-Chen Chang
- Giorgio Perino
- Madhur Shetty
- Takahiro Yamazaki
- Wanxia Li Tsai
- Aleksandra M. Urbanska
- J. Mauricio Calvo-Calle
- [email protected]
- Shakti Ramsamooj
- Diego Vergani
- Giorgina Mieli-Vergani
- Benedetta Terziroli Beretta-Piccoli
- Massimo Gadina
- Cristina Montagna
- Marcus DaSilva Goncalves
- Federica Sallusto
- Lorenzo Galluzzi
- Rajesh K. Soni
- Lawrence J. Stern
- Laura Santambrogio
19 Aug 2022
NO ACCESS

Metabolic insults elicit epitope-dependent immune autoreactivity to PDIA3, aggravating hepatic damage in type 2 diabetes.

Abstract

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver ...

Size-dependent activation of CAR-T cells

- Qian Xiao
- Xinyan Zhang
- Liqun Tu
- Jian Cao
- Christian S. Hinrichs
- Xiaolei Su
05 Aug 2022
Free

The size difference between CAR-antigen pair and CD45 regulates CAR-T activation.

Abstract

As the targets of chimeric antigen receptor (CAR)–T cells expand to a variety of cancers, autoimmune diseases, viral infections, and fibrosis, there is an increasing demand for identifying new antigens and designing new CARs that can be effectively ...

Asymmetrical forward and reverse developmental trajectories determine molecular programs of B cell antigen receptor editing

- Michael K. Okoreeh
- Domenick E. Kennedy
- Akinola Olumide Emmanuel
- Margaret Veselits
- Azam Moshin
- Robert H. Ladd
- Steven Erickson
- Kaitlin C. McLean
- Brianna Madrigal
- David Nemazee
- Mark Maienschein-Cline
- Malay Mandal
- Marcus R. Clark
05 Aug 2022
NO ACCESS

The molecular pathways of BCR editing consist of a unique epigenetic landscape activated and amplified by both BCR and CXCR4 signals.

Abstract

During B lymphopoiesis, B cell progenitors progress through alternating and mutually exclusive stages of clonal expansion and immunoglobulin (Ig) gene rearrangements. Great diversity is generated through the stochastic recombination of Ig gene segments ...

Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity

- Anna Purcarea
- Sebastian Jarosch
- Jack Barton
- Simon Grassmann
- Ludwig Pachmayr
- Elvira D’Ippolito
- Monika Hammel
- Anna Hochholzer
- Karolin I. Wagner
- Joost H. van den Berg
- Veit R. Buchholz
- John B. A. G. Haanen
- Dirk H. Busch
- Kilian Schober
12 Aug 2022
NO ACCESS

Tumor-reactive TCRs with high protective capacity circulating in peripheral blood are characterized by a signature of recent activation.

Abstract

T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains ...

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

- William Rae
- John M. Sowerby
- Dorit Verhoeven
- Mariam Youssef
- Prasanti Kotagiri
- Natalia Savinykh
- Eve L. Coomber
- Alexis Boneparth
- Angela Chan
- Chun Gong
- Machiel H. Jansen
- Romy du Long
- Giorgia Santilli
- Ilenia Simeoni
- Jonathan Stephens
- Kejia Wu
- Marta Zinicola
- Hana Lango Allen
- Helen Baxendale
- Dinakantha Kumararatne
- Effrossyni Gkrania-Klotsas
- Selma C. Scheffler Mendoza
- Marco Antonio Yamazaki-Nakashimada
- Laura Berrón Ruiz
- Cesar Mauricio Rojas-Maruri
- Saul O. Lugo Reyes
- Paul A. Lyons
- Anthony P. Williams
- Daniel J. Hodson
- Gail A. Bishop
- Adrian J. Thrasher
- David C. Thomas
- Michael P. Murphy
- Timothy J. Vyse
- Joshua D. Milner
- Taco W. Kuijpers
- Kenneth G. C. Smith
12 Aug 2022
NO ACCESS

Reduced TRAF3 in humans results in B cell hyperactivity and T cell defects predisposing to infections, autoimmunity, and malignancy.

Abstract

Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an ...

Cis interactions between CD2 and its ligands on T cells are required for T cell activation

- Bin Li
- Yan Lu
- Ming-Chao Zhong
- Jin Qian
- Rui Li
- Dominique Davidson
- Zhenghai Tang
- Kaiwen Zhu
- Jérémy Argenty
- Anne Gonzalez de Peredo
- Bernard Malissen
- Romain Roncagalli
- André Veillette
05 Aug 2022
NO ACCESS

T cell activation depends on cis interactions between CD2 and its ligands CD48 and CD58 on T cells.

Abstract

CD2 is largely described to promote T cell activation when engaged by its ligands, CD48 in mice and CD58 in humans, that are present on antigen-presenting cells (APCs). However, both CD48 and CD58 are also expressed on T cells. By generating new knockout ...

TCR-engineered iNKT cells induce robust antitumor response by dual targeting cancer and suppressive myeloid cells

- Gloria Delfanti
- Filippo Cortesi
- Alessandra Perini
- Gaia Antonini
- Laura Azzimonti
- Claudia de Lalla
- Claudio Garavaglia
- Mario L. Squadrito
- Maya Fedeli
- Michela Consonni
- Silvia Sesana
- Francesca Re
- Haifa Shen
- Paolo Dellabona
- Giulia Casorati
19 Aug 2022
Free

Redirecting iNKT cells against cancer cells by TCR engineering restrains immunosuppression and promotes strong antitumor responses.

Abstract

Adoptive immunotherapy with T cells engineered with tumor-specific T cell receptors (TCRs) holds promise for cancer treatment. However, suppressive cues generated in the tumor microenvironment (TME) can hinder the efficacy of these therapies, prompting ...

Editors' Choice

Decoding moms’ rules of engagement with cytomegalovirus

- David R. Martinez
05 Aug 2022
Free

Cytomegalovirus-infected moms with antibodies that can engage the immune system via FcγR are less likely to congenitally transmit the virus.

Abstract

Cytomegalovirus-infected moms with antibodies that can engage the immune system via FcγR are less likely to congenitally transmit the virus.

The role of sex in exhaustion

- Sarah E. Henrickson
05 Aug 2022
Free

Androgen receptor signaling promotes CD8 T cell exhaustion that diminishes antitumor immunity.

Abstract

Androgen receptor signaling promotes CD8 T cell exhaustion that diminishes antitumor immunity.

Reports

Antibodies induced by an ancestral SARS-CoV-2 strain that cross-neutralize variants from Alpha to Omicron BA.1

- Ian W. Windsor
- Pei Tong
- Olivia Lavidor
- Ali Sanjari Moghaddam
- Lindsay G.A. McKay
- Avneesh Gautam
- Yuezhou Chen
- Elizabeth A. MacDonald
- Duck Kyun Yoo
- Anthony Griffths
- Duane R. Wesemann
- Stephen C. Harrison
12 Aug 2022
Open Access

Structures of SARS-CoV-2 spike-bound antibodies from Wuhan strain infection show features needed to neutralize variants of concern.

Abstract

Neutralizing antibodies that recognize the SARS-CoV-2 spike glycoprotein are the principal host defense against viral invasion. Variants of SARS-CoV-2 bear mutations that allow escape from neutralization by many human antibodies, especially those in ...