Peripheral T cell lymphomas (PTCLs) are a diverse group of aggressive malignancies that arise from mature, post-thymic T cells. Recent genomic and mechanistic studies reveal that these cancers frequently 'hijack' signall...Peripheral T cell lymphomas (PTCLs) are a diverse group of aggressive malignancies that arise from mature, post-thymic T cells. Recent genomic and mechanistic studies reveal that these cancers frequently 'hijack' signalling pathways that normally govern T cell activation at the immunological synapse. Specifically, numerous gain-of-function alterations in TCR proximal regulators and mediators of antigen-induced NF-κB activation, as well as mutations or overexpression of co-stimulatory receptors and dysregulated cytokine receptor signalling, promote the constitutive proliferation and survival of malignant clones. Conversely, loss-of-function mutations in PDCD1 or disruption of PD1-mediated inhibitory control, coupled with altered metabolic and epigenetic reprogramming, have emerged as a major tumour-suppressor mechanism in PTCL pathogenesis. This framework conceptualizes PTCLs as 'cancers of aberrant immune synapse signalling pathways' and posits that genetic dissection of PTCL pathogenesis can uncover fundamental aspects of T cell biology to guide the design of safer, more effective next-generation T cell therapies.
Over the past 20 years, the limited efficacy of CD8⁺ T cell-based vaccines against viruses in clinical trials has shifted attention away from such strategies. However, recent findings have brought renewed appreciation fo...Over the past 20 years, the limited efficacy of CD8⁺ T cell-based vaccines against viruses in clinical trials has shifted attention away from such strategies. However, recent findings have brought renewed appreciation for the central importance of CD8⁺ T cells in controlling both acute and chronic viral infections and in preventing severe or progressive disease. This work highlights shared features, such as effector functions and stemness properties, of effective CD8⁺ T cell responses against diverse viruses such as SARS-CoV-2 and HIV. A deeper understanding and simpler interpretation of the functional workings of CD8⁺ T cell-mediated immunity, combined with advances in immunological and biotechnological tools, are opening new avenues for eliciting optimal T cell responses, both for prophylactic and for therapeutic applications. Collectively, these developments revive optimism that vaccines and immunotherapies designed to harness robust CD8⁺ T cell responses could have a major role in combating emerging viral threats and in achieving long-term suppression of persistent infections such as HIV-1 to undetectable levels.
The engineering of chimeric antigen receptor (CAR) T cells has evolved from first-generation constructs to sophisticated armoured CAR T cells of the fourth generation. These advanced cellular constructs are engineered to...The engineering of chimeric antigen receptor (CAR) T cells has evolved from first-generation constructs to sophisticated armoured CAR T cells of the fourth generation. These advanced cellular constructs are engineered to co-express cytokines, chemokines or other immunomodulatory factors alongside CARs, aiming to enhance the efficacy, safety and persistence of CAR T cells within the tumour microenvironment. In particular, the potential for reversion of immunosuppression may allow for the treatment of solid tumours, which are in need of new therapeutic options. Here, we explore clinical and preclinical findings with cytokine-enhanced CAR T cells and discuss strategies for conditional cytokine secretion to mitigate systemic toxicity.
Kwon DI, Bhagchandani SH, Ehrenzeller SA
… +1 more, Iwasaki A
Nat Rev Immunol
· 2026 Jul · PMID 41699393
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Mucosal surfaces are primary entry sites for many infectious pathogens, yet parenteral vaccination alone often fails to elicit effective mucosal immunity. Mucosally delivered vaccines offer a promising strategy for reinf...Mucosal surfaces are primary entry sites for many infectious pathogens, yet parenteral vaccination alone often fails to elicit effective mucosal immunity. Mucosally delivered vaccines offer a promising strategy for reinforcing frontline defences and inducing localized, pathogen-specific immune responses. Recent studies indicate that mucosal vaccines elicit tissue-resident memory T and B cells, along with robust local antibody secretion, to prevent infection and transmission. However, achieving sterilizing immunity at mucosal sites proves challenging owing to the complex immune environments consisting of epithelial barriers, varying mucus composition, pH differences and hormonal influences. In this Review, we outline how specialized immune-inductive and effector mechanisms across distinct mucosal compartments contribute to protective immunity and discuss emerging strategies to harness multilayered mucosal immunity to develop safe, effective vaccines that elicit durable protection.
Older individuals exhibit distinct biochemical and functional changes in their immune cells that can lead to chronic inflammation, reduced immunity to pathogens and organ dysfunction. Immune cells from older individuals...Older individuals exhibit distinct biochemical and functional changes in their immune cells that can lead to chronic inflammation, reduced immunity to pathogens and organ dysfunction. Immune cells from older individuals acquire dysfunctional immunosenescent phenotypes that are classified as inflammatory, exhausted or senescent. Key molecular mechanisms, commonly described as hallmarks of ageing, drive the development of these phenotypes through both cell-autonomous and non-autonomous mechanisms. Importantly, the ageing immune system can drive multi-organ dysfunction and systemic ageing, suggesting that improving immune function in older individuals could have significant health benefits. Here, we review the effects of ageing on various immune cell subsets in mice and humans. We describe the molecular mechanisms that drive these functional changes and their effects on both lymphoid and non-lymphoid organs. We also discuss therapeutic approaches to improve the function of the ageing immune system to increase resilience and extend healthspan.
Fibrosis is a complex disorder characterized by the excessive deposition of extracellular matrix, which disrupts normal tissue architecture and compromises organ function. Fibrosis can affect any organ, with pulmonary fi...Fibrosis is a complex disorder characterized by the excessive deposition of extracellular matrix, which disrupts normal tissue architecture and compromises organ function. Fibrosis can affect any organ, with pulmonary fibrosis being one of the most common and life-threatening forms. Despite marked research efforts, effective antifibrotic therapies remain limited, largely due to an incomplete understanding of the underlying disease mechanisms. At the centre of fibrotic processes are fibroblasts, which are tissue-resident mesenchymal cells responsible for extracellular matrix production, tissue remodelling, wound healing and fibrosis. For decades, the biology of fibroblasts remained poorly understood, but advances in single-cell sequencing have recently provided deeper insights into their heterogeneity, plasticity and functional diversity. These insights have prompted renewed efforts to identify the core regulatory programmes that govern fibroblast states in health and disease. In this Review, we examine how immunological, mechanical and metabolic regulators influence fibroblast function in fibrosing interstitial lung diseases. We show how loss of stromal regulation through chronic inflammation, immune dysfunction, altered tissue biomechanics and metabolic stress can tip the balance from successful tissue repair to progressive fibrosis.