bims-maitce 2025-03-23 papers

Issue of 2025–03–23
five papers selected by
Andy E. Hogan, Maynooth University

J Neuroinflammation. 2025 Mar 20. 22(1): 90

MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice.

Yuanyue Zhang, Zhi Yang, Na Jiang, Xiaosheng Tan, Peng Jiang, Gaoyuan Cao, Qi Yang.

BACKGROUND: The role of immune cells in neurodegeneration remains incompletely understood. Accumulation of misfolded tau proteins is a hallmark of neurodegenerative diseases. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. However, the role of MAIT cells in tau-related neuroinflammation and neurodegeneration remains unknown.
METHODS: Flow cytometry analysis was performed to examine MAIT cells in human Tau P301S transgenic mice. Tau pathology, hippocampus atrophy, meningeal integrity, and microglial gene expression were examined in Mr1-/- P301S mice that lacked MAIT cells and control P301S transgenic mice, as well as Mr1-/- P301S mice with adoptive transfer of MAIT cells.
RESULTS: The meninges of P301S mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1-/-P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1+/+P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1-/- P301S mice. Meningeal barrier integrity was compromised in Mr1-/-P301S mice, but not in control Mr1+/+P301S mice. A distinctive microglia subset with a proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1-/-P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related to ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1-/- P301S mice.
CONCLUSIONS: Our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

DOI: https://doi.org/10.1186/s12974-025-03413-7

Transl Oncol. 2025 Mar 14. pii: S1936-5233(25)00089-0. [Epub ahead of print]55 102358

Leveraging machine learning for integrative analysis of T-cell receptor repertoires in colorectal cancer: Insights into MAIT cell dynamics and risk assessment.

Romi Goldner Kabeli, Ben Boursi, Alona Zilberberg, Sol Efroni.

This study investigates the T-cell receptor (TCR) repertoires in colorectal cancer (CRC) patients by analyzing three distinct datasets: one bulk sequencing dataset of 205 patients with various tumor stages, all newly diagnosed at Sheba Medical Center between 2017 and 2022, with minimal recruitment in 2014 and 2016, and two (public) single-cell sequencing datasets of 10 and 12 patients. Despite the significant variability in the TCR repertoire and the low likelihood of sequence overlap, our analysis reveals an interesting set of TCR sequences across these data. Notably, we observe elevated presence of mucosal-associated invariant T (MAIT) cells in both metastatic and non-metastatic patients. Furthermore, we identify nine identical TCR alpha and TCR beta pairs that appear in both single-cell datasets, with 13 out of 18 sequences from these sequences also appearing in the bulk data. Clinical risk analysis over the bulk dataset, using a subset of these unique sequences, demonstrates a correlation between TCR repertoire disease stage and risk. These findings enhance our understanding of the TCR landscape in CRC and underscore the potential of TCR sequences as biomarkers for disease outcome.

Keywords: CRC; Deep learning; MAIT cells; Risk assessment; T cell repertoire; TCR

DOI: https://doi.org/10.1016/j.tranon.2025.102358

Cytometry A. 2025 Mar 17.

OMIP-112: 42-Parameter (40-Color) Spectral Flow Cytometry Panel for Comprehensive Immunophenotyping of Human Peripheral Blood Leukocytes.

Laurien A Waaijer, Bram van Cranenbroek, Hans J P M Koenen.

Profiling the human immune system is essential to understanding its role in disease, but it requires advanced and novel technologies. Spectral flow cytometry (SFM) enables deep profiling at the single-cell level. It is able to detect many fluorescent parameters within one measurement; therefore, it is vastly useful when patient material is limited. However, designing and analyzing these high-dimensional datasets remains complex. We optimized a 42-parameter panel (40 commercially available fluorochromes, one stacked fluorochrome and an autofluorescent (AF) parameter) that enables the identification of innate and adaptive immune cell composition. It is the first 42-parameter panel that is optimized on peripheral whole blood, and it outperforms other published OMIPs of 40 colors in terms of complexity. With this panel, we are able to identify neutrophils, basophils, eosinophils, monocytes, dendritic cells, CD4 T cells, CD8 T cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, B cells, NK cells, dendritic cells, and innate lymphoid cells (ILCs). Furthermore, with the utilization of co-stimulatory, checkpoint, activation, homing, and maturation markers, this panel enables deeper phenotyping. Within one measurement, more than 80 distinct immune cell subsets were identified by FlowSOM and annotated manually. In conclusion, with this high-dimensional SFM panel, we aim to generate immune profiles to understand disease and monitor therapy response.

Keywords: OMIP; Sony ID7000; computational analysis; deep immunophenotyping; full spectrum; high‐dimensional flow cytometry; peripheral blood leukocytes; spectral

DOI: https://doi.org/10.1002/cyto.a.24927

Curr Opin Pulm Med. 2025 Mar 19.

Mucosal-associated invariant T-cells in pulmonary pathophysiology.

Jéssica Kamiki, Carolina M Gorgulho, Joana R Lérias, Markus J Maeurer.

PURPOSE OF REVIEW: Mucosal-associated invariant T-cells (MAIT) have been associated with lung cancer and pulmonary infections. The treatment of patients with cancer or infections includes host-directed therapies (HDTs). MAIT play a role in shaping the 'milieu interne' in cancer and infections and this review addresses the biology of MAIT in pulmonary pathophysiology.
RECENT FINDINGS: MAIT represent an attractive target for therapy in pulmonary malignancies and infections. T-cells are often difficult to exploit therapeutically due to the diversity of both T-cell receptor (TCR) repertoire and its ligandome. MAIT-cells are restricted by the major histocompatibility complex class I-related gene protein (MR1) that presents nondefined tumor-associated targets, bacterial products, vitamin and drug derivates. Due to their plasticity in gene expression, MAIT are able to conversely switch from IFN-γ to IL-17 production. Both cytokines play a key role in protective immune responses in infections and malignancies. MAIT-derived production of interleukin (IL)-17/TGF-β shapes the tumor micro-environment (TME), including tissue re-modelling leading to pulmonary fibrosis and recruitment of neutrophils. MAIT contribute to the gut-lung axis associated with clinical improved responses of patients with cancer to checkpoint inhibition therapy. MAIT are at the crossroad of HDTs targeting malignant and infected cells. Clinical presentations of overt inflammation, protective immune responses and tissue re-modeling are reviewed along the balance between Th1, Th2, Th9, and Th17 responses associated with immune-suppression or protective immune responses in infections.
SUMMARY: MAIT shape the TME in pulmonary malignancies and infections. Drugs targeting the TME and HDTs affect MAIT that can be explored to achieve improved clinical results while curbing overt tissue-damaging immune responses.

DOI: https://doi.org/10.1097/MCP.0000000000001163

Brain. 2025 Mar 17. pii: awaf096. [Epub ahead of print]

Activated αβ T- and reduced mucosa-associated invariant T cells in LGI1- and CASPR2-encephalitis.

in cooperation with the EMC-AIE Study group

Anti-Leucine-rich glioma inactivated-1 (LGI1) and anti-contactin-associated-protein-2 (CASPR2) autoimmune encephalitis (AIE) are common and characterized by pathogenic antibodies targeting neuronal autoantigens. However, the drivers of the antibody-secreting cells (ASC) and involvement of T cells remain unresolved. We performed single cell RNA-sequencing of fresh cerebrospinal fluid (CSF) and parallel blood samples of 15 patients with LGI1- (n=9) and CASPR2-AIE (n=6) compared to control patients (multiple sclerosis (MS) n=15, idiopathic intracranial hypertension (IIH) n=18). We validated our observations in independent cohorts using flow cytometry of CSF and blood. We confirmed autoantibody specificity using recombinant human monoclonal antibodies. Compared to IIH and MS controls, we observed clonal CSF-specific ASC expansion in LGI1/CASPR2-AIE despite mostly normal CSF findings. ASCs were dominantly plasmablasts and transcribed IgG4 and IgG1/2 heavy chains. Expanded clones showed signs of affinity maturation and bound the respective neuronal autoantigen. Within CD4 and CD8 T cell clusters, CD4 and CD8 central memory T cells were activated, clonally restricted and expanded. T cell clones were often shared between CSF and blood. We also observed a shift of NK cells and loss of mucosa-associated invariant T (MAIT) cells in the CSF of LGI1- and blood of LGI1- and CASPR2-AIE compared to IIH and MS controls. Indeed, MAIT-like T cells were detected in autopsy brains of LGI1 and CASPR2-AIE patients and mice lacking MAIT cells displayed an increased antibody seroconversion and higher titers following active LGI1-/CASPR2 immunization. Our data (1) confirms the intrathecal antigen-specific plasma cell expansion in LGI1- and CASPR2-AIE in a large cohort of untreated AIE patients, (2) suggests that activated and expanded central memory CD4 and CD8 T cells in the CSF participate in disease pathogenesis and (3) for the first time implicates invariant T cell receptor expressing lymphocytes in the brain, CSF and blood in disease pathogenesis.

Keywords: MAIT; autoimmune encephalitis; contactin-associated protein 2; flow cytometry; leucin-rich glioma inactivated 1; single cell transcriptomics

DOI: https://doi.org/10.1093/brain/awaf096