Nature Reviews Immunology最新文献

Immune cells can exchange membrane-bound molecules via horizontal protein transfer, a poorly understood process termed trogocytosis. Barbera et al. now show that chimeric antigen receptor (CAR)-engineered T cells can transfer their CARs to T cells and other cells by trogocytosis in vivo. CARs on recipient T cells seemed to be functional, as isolated recipient cells were able to kill target cells. Trogocytosis did not depend on a cognate binding partner for the transferred protein, as had been proposed previously. Instead, the probability of a horizontal CAR transfer was determined by its transmembrane domain and its likelihood to localize to the tips of microvilli. These findings have important implications for CAR design.

The arrival of the Omicron variant of SARS-CoV-2 in late 2021 marked a major shift during the COVID-19 pandemic, as the virus acquired dozens of mutations in its spike protein compared with earlier variants. Now, an epidemiological study in Nature shows that it also led to a shift in the protective effect of natural infection against reinfection: pre-Omicron, infection provided stable and durable protection, whereas infection during the Omicron era provided protection for only a short time. The authors conclude that this reflects a shift in evolutionary pressure from intrinsic transmissibility to immune escape. Moreover, the finding highlights the importance of regular updates of COVID-19 vaccines.

Cytotoxic T lymphocytes (CTLs) in tumours are often dysfunctional. Bréart et al. investigated the association between cytokines and CTLs in human tumours and found a correlation between IL27 expression and CTL infiltration. In syngeneic mouse models, treatment with an IL-27-encoding plasmid or half-life-enhanced IL-27, with or without anti-PD-L1, improved tumour rejection without overt toxicity. Single-cell RNA sequencing of mouse CTLs showed that IL-27 induces the expression of cytotoxicity genes, such as Gzmb, and downregulates genes linked to exhaustion, such as Tox. In patients with metastatic urothelial bladder carcinoma or non-small-cell lung cancer, high IL-27 expression was associated with improved responses to PD-L1-targeted therapy, and in vitro exhaustion assays with human CTLs showed that IL-27 promotes the differentiation of cytotoxic and effector memory T cells while suppressing dysfunction-associated markers. Overall, IL-27 seems to support CTL fitness and cytotoxicity and may be an attractive therapeutic target in cancer.

Antiretroviral therapy (ART) has markedly improved the life-expectancy of people living with HIV. However, during both HIV infection of humans and simian immunodeficiency virus infection of macaques, virus replication almost invariably rebounds upon ART interruption, due to the long-term persistency of a pool of latently infected cells harbouring integrated, replication-competent virus (known as the virus reservoir). Solving this ‘HIV reservoir problem’ is the key to achieving a cure (or at least a persistent remission) for HIV infection. Here, we summarize the key scientific evidence supporting the hypothesis that host immune responses, including those mediated by CD8⁺ T cells, B cells, antibodies and innate immune cells, affect the size, clonality, and cellular, tissue and organ distribution of the HIV reservoir. Importantly, we believe that any solution to the ‘reservoir problem’ must address not only the multifaceted interactions between HIV and the host immune system, but also the complex interplay between the immunobiology of memory CD4⁺ T helper cells (which form the main virus reservoir) and the molecular mechanisms that regulate HIV latency and reactivation. These concepts provide the rationale to develop new, immune-based approaches to ‘cure’ HIV infection; we review recent efforts to develop such therapies and their efficacy (or lack thereof) in disrupting the establishment and/or persistence of the virus reservoir in preclinical animal models and human clinical trials.

B cells have long been understood to be drivers of both humoral and cellular immunity. Recent advances underscore this importance but also indicate that in infection, inflammatory disease and cancer, B cells function directly at sites of inflammation and form tissue-resident memory populations. The spatial organization and cellular niches of tissue B cells have profound effects on their function and on disease outcome, as well as on patient response to therapy. Here we review the role of B cells in peripheral tissues in homeostasis and disease, and discuss the newly identified cellular and molecular signals that are involved in regulating their activity. We integrate emerging data from multi-omic human studies with experimental models to propose a framework for B cell function in tissue inflammation and homeostasis.

A recent Review in this journal by Comerford and McColl¹ discussed how atypical chemokine receptors (ACKRs) have emerged as important regulators of chemokines, both in the immune system and beyond. Unlike classical chemokine receptors, ACKRs do not couple to G proteins and thus do not induce cell migration in response to chemokines. Instead, ACKRs regulate chemokine availability in defined tissue microenvironments through ligand sequestration, transport, internalization and delivery for degradation. This year marks the tenth anniversary of the systematic classification of ACKRs by the nomenclature committee of the International Union of Basic and Clinical Pharmacology (IUPHAR)². Until recently, this subfamily comprised four receptors (ACKR1–ACKR4), but as discussed in the Review, additional molecules are being investigated as potential new members of the ACKR family. In October 2024, one of these molecules, GPR182, was officially recognized by the IUPHAR as ACKR5 (ref. ³) (Fig. 1).

Atypical chemokine receptors (ACKRs) are expressed on different types of endothelial or immune cells. ACKR1 and ACKR2 bind a broad spectrum of inflammatory chemokines that they share with CXCR1–CXCR3 and CCR1–CCR5. ACKR3 binds the homeostatic chemokine CXCL12, which it shares with CXCR4, and the inflammatory CXCL11, shared with CXCR3. ACKR4 interacts with a limited number of mainly homeostatic chemokines that it shares with CCR4, CCR6, CCR7 and CCR9. ACKR5 binds a wide range of XC, CC and CXC chemokines shared with CCR1–CCR10, CXCR2–6 and XCR1. ACKR3 and ACKR5 also bind non-chemokine ligands. For CXCL11, it is depicted in a grey box above ACKR2 as it is an antagonist.

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