bims-maitce 2025-12-28 papers

Issue of 2025–12–28
four papers selected by
Andy E. Hogan, Maynooth University

Immunology. 2025 Dec 21.

Signal Transducer and Activator of Transcription (STAT) Proteins Regulate Mucosal-Associated Invariant T (MAIT) Cell Function.

Olivia J Cheng, Eimear K Ryan, Michael Bennett, Christy Clutter, Jackson G Cacioppo, Jeffrey Aubé, Andy E Hogan, Daniel T Leung.

Mucosal-Associated Invariant T (MAIT) cells are a subset of T cells with potential for rapid cytotoxic and inflammatory functions. Dysregulation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway, particularly involving STAT1 and STAT3, has been implicated in MAIT cell dysfunction in certain diseases. However, the transcriptional mechanisms regulating their effector functions, particularly the role of various STAT proteins, remain poorly understood. Using RNA sequencing and proteomics data, and experimental validation through in vitro assays using MAIT-specific stimulation and small molecule inhibitors, we analysed the impact of STAT1, STAT3 and STAT5 on MAIT cell activation and function. Flow cytometric analysis was used to assess the functional implications of manipulating STAT proteins and the metabolic regulator HIF1α in MAIT cells. Our findings show that enhanced STAT1 activity negatively impacts MAIT cell effector functions, including granzyme B and interferon-γ expression, while STAT3 and STAT5 are essential for promoting MAIT cell activation, function and glycolytic responses. Additionally, we identify HIF1α as a key regulator of these processes, suggesting that metabolic reprogramming plays a critical role in MAIT cell activation and function. This study highlights the critical roles of STAT1, STAT3, STAT5 and HIF1α in regulating MAIT cell effector functions, expanding our understanding of the molecular mechanisms underlying MAIT cell dysfunction. Our work lays the foundation for future research and applications aimed at modulating MAIT cell activity in immune-related diseases and malignancies.

Keywords: Janus kinase/signal transducer and activator of transcription (JAK–STAT); metabolism; mucosal‐associated invariant T (MAIT) cells; regulation

DOI: https://doi.org/10.1111/imm.70086

Antibodies (Basel). 2025 Dec 08. pii: 105. [Epub ahead of print]14(4):

Breakthrough for Anticancer Immunotherapy: Current Advances in Manufacturing Protocols of Chimeric Antigen Receptor-Based Therapies.

Yuxin Qian, Weiwei Ma, Xiao-Ning Xu.

Chimeric antigen receptor (CAR)-based immunotherapy has emerged as a transformative strategy in anticancer treatment, driven by advances in CAR construct design, manufacturing platforms, and expansion to diverse immune cell types. The landmark success of CD19-targeted CAR-T cell therapy in B cell malignancies has paved the way for broader clinical applications. As of 2025, the U.S. FDA has approved multiple autologous CAR-T products, underscoring their therapeutic promise. However, challenges persist, including cytokine release syndrome (CRS), neurotoxicity, product inconsistency, and the high cost and complexity of cell manufacturing. Variations in cell source, gene delivery methods, expansion protocols, and CAR design significantly influence the safety, efficacy, and scalability of these therapies. In this review, we comprehensively examine the current advances in manufacturing protocols for CAR-modified T cells, natural killer (NK) cells, and unconventional T cell subsets, including γδ T, invariant natural killer T (iNKT), and mucosal-associated invariant T (MAIT) cells. We also highlight emerging innovations such as in vivo CAR-T generation and off-the-shelf allogeneic approaches. By integrating updated strategies with a critical evaluation of current limitations, this review aims to support the development of standardized, robust, and accessible CAR-based immunotherapies.

Keywords: antibody-derived scFv; cancer immunotherapy; cell manufacturing; chimeric antigen receptor (CAR)

DOI: https://doi.org/10.3390/antib14040105

Alzheimers Dement. 2025 Dec;21 Suppl 1 e102122

Basic Science and Pathogenesis.

Wassim Elyaman.

BACKGROUND: Aging is the greatest risk factor for Alzheimer's disease (AD), with immunosenescence-the gradual decline in immune system function with age-playing a critical role in disease susceptibility. As individuals age, brain-resident microglia and circulating immune cells undergo functional changes that can compromise their ability to respond effectively to emerging pathology. Dysregulated immune responses, driven by immunosenescence, may exacerbate neuroinflammation and accelerate AD progression. Despite growing recognition of the link between aging, immune dysfunction, and neurodegeneration, no interventions specifically target the impact of immunosenescence during the prodromal stage of AD. Profiling immune changes associated with aging and their connection to early AD biomarkers could uncover druggable pathways, offering transformative opportunities to prevent or delay disease onset.
METHOD: To identify immune mechanisms underpinning preclinical AD, we performed single-cell RNA, and T cell and B cell receptor sequencing, capturing >439,000 transcriptomes from 205 participants (ages 29-81) in the Offspring Study of Racial and Ethnic Disparities in Alzheimer's Disease. Plasma proteomics data were also obtained from 86 participants. Immune cell phenotypes and gene expression were correlated with AD biomarkers, including plasma proteins, cortical thickness via MRI, cognitive performance, and parental AD diagnosis.
RESULT: Our analysis revealed distinct immune signatures associated with cortical integrity. B cell proportions positively correlated with left hemisphere cortical thickness, while CD8+ T cell proportions showed an inverse association. Within the CD8+ T cell population, naïve and mucosal-associated invariant T (MAIT) cells were enriched in individuals with preserved cortical structure, whereas effector memory cells were reduced. Transcriptomic profiling revealed downregulation of cytotoxicity, antigen processing, and antigen presentation pathways in T cells from individuals with greater cortical thickness and better cognitive function. Additionally, we identified an age-associated decline in T cell receptor (TCR) repertoire diversity and a reduction in MAIT cell proportions, highlighting the impact of immunosenescence on adaptive immune function and its potential link to neurodegenerative risk.
CONCLUSION: This study highlights the role of aging-related immunosenescence in shaping neuroimmune interactions linked to Alzheimer's disease risk. These findings underscore age-driven immune dysregulation as a key contributor to disease susceptibility and suggest potential targets for immune-based therapies to mitigate progression.

DOI: https://doi.org/10.1002/alz70855_102122

Front Immunol. 2025 ;16 1667888

Changes in circulating NK and innate-like T cells in type 1 and type 2 diabetes.

Marina Loguinova, Nikita Sergeev, Margarita Samsonova, Alyona Sorokina, Dmitry Grebennikov, Ivan Golodnikov, Anna Goncharenko, Gennady Bocharov, Dmitry Laptev, Rita Khusainova, Ildar Minniakhmetov, Marina Shestakova, Ivan Dedov, Natalia Mokrysheva.

Background: Inflammatory responses that accompany the progression of type 1 (T1D) and type 2 diabetes mellitus (T2D) are fundamentally distinct in their underlying nature. T1D is predominantly driven by autoimmune-mediated inflammation, whereas T2D is characterized by a chronic, low-grade metabolic inflammation. A growing body of evidence has highlighted the involvement of natural killer (NK) cells in pathophysiology of both forms of diabetes; nevertheless, the precise mechanisms and the roles played by specific NK cell subsets remain incompletely understood.
Methods: Multicolor flow cytometry was used to identify several NK and innate-like T cell subpopulations in peripheral blood of patients with adult-onset T1D (n=23) and T2D (n=14) in comparison to healthy volunteers (n=24). Subset identification was based on expression of functional antigens (CD16 and CD56), co-receptors (CD8 and CD38), inhibitory receptors (NKG2A and CD161), and transcription factor EOMES. Quantitative analysis using Spearman's rank correlation coefficients was performed to identify possible association between immune and clinical parameters and to rank the clinical parameters with respect to the number of connections with immune cell populations.
Results: T1D was accompanied by a reduction in overall NK cells and their dominant cytolytic CD56dimCD16bright subpopulation. Also a 50% increase in frequency of CD8+ NK cells was observed together with a growth of CD8+CD38+, CD8+CD161+, CD8+NKG2A+, and CD8+EOMES+ NK subsets. T2D was associated with a more than twofold decrease in the frequency of MAIT cell subset within CD8+ T cell population. Correlation analysis of the obtained data set revealed quantitative relationships between immune status parameters and clinical indicators, highlighting the involvement of NK cell subsets and innate-like T cells in shaping the phenotype of the pathological process and their complex role in regulating the immunopathogenesis of T1D and T2D.
Conclusion: In this pilot study, we provide evidence that different subpopulations of NK cells and innate-like T cells are involved in the immunopathogenesis of T1D and T2D, through a decline in the control of immune reactivity in T1D, while sustaining chronic metainflammatory responses in T2D. A critical elevation of CD8+ NK cells was associated with T1D, while loss of circulating MAIT cells was a hallmark of T2D.

Keywords: CD161; CD38; NK cells; NK8+; NKG2A; autoimmune inflammation; innate-like T cells; type 1 and type 2 diabetes mellitus

DOI: https://doi.org/10.3389/fimmu.2025.1667888