bims-maitce 2025-07-20 papers

Issue of 2025–07–20
four papers selected by
Andy E. Hogan, Maynooth University

Immunobiology. 2025 Jun 27. pii: S0171-2985(25)00225-6. [Epub ahead of print]230(4): 153091

Diversity and hallmarks of metabolites surveyed by MR1.

Mucosal-associated invariant T (MAIT) cells are one of the innate T cell subset. They are known to contribute to anti-bacterial response by recognizing bacterial components with invariant TCRs which are presented on a monomorphic antigen presenting molecule, MHC related protein 1(MR1). After years of uncertainty about the molecular entity of this bacterial antigen, they were recognized as vitamin B metabolites in 2012, and identified as 5-OP-RU in 2014. Recently, MR1 was found to contain a broad ligand-binding pocket, allowing recognition of compounds with various structures. In this review article, we will summarize the history of MR1 ligand discovery and discuss the potential new ligand structures that may uncover previously-unappreciated MAIT cell functions.

Keywords: Antigen presentation; Bacterial metabolite; Endogenous metabolite; MAIT cell; MR1

DOI: https://doi.org/10.1016/j.imbio.2025.153091

Blood Adv. 2025 Jul 16. pii: bloodadvances.2025015976. [Epub ahead of print]

Immune cells display an abnormal maturation and a pro-inflammatory profile in telomere biology disorders.

Willian R Gomes, Shan Hama, Giorgio Napolitani, Amandine Tan, Luiz Fernando B Catto, Flavia S Donaires, Barbara A Santana, Vinicius S Carvalho, Edson Z Martinez, Antonio Condino-Neto, Mohammad M Karimi, Ghulam J Mufti, Rodrigo T Calado.

Pathogenic germline variants causing excessive telomere shortening may result in bone marrow failure, hematopoietic malignancy, and extramedullary complications, such as pulmonary fibrosis, liver cirrhosis, and solid tumors. Patients with short telomeres also develop immunodeficiency with low CD4+ T cells and impaired general immunosurveillance, particularly against solid neoplasms. We investigated a broad spectrum of lymphocyte subsets and myeloid immune cells from human patients with telomere biology disorders (TBDs) and matched healthy volunteers to understand further how the immune system is affected by telomere dysfunction. We employed mass cytometry (CyTOF) for deep-immunophenotyping peripheral blood mononuclear cells (PBMCs), followed by high-dimensional data analysis. Cytokines, chemokines, and growth factors were assessed in serum. Our results showed profound immune alterations in TBD beyond those observed in aging, with low naïve lymphocytes and thymic hypofunction. We further observed that T helper subsets were markedly skewed, with an inverted TH2/TH1 ratio and low TH17 and TH17.1 levels. T cell activation and exhaustion markers were upregulated, whereas circulating mucosal-associated invariant T (MAIT) cells were significantly decreased and overactivated. Several serum cytokine levels were positively correlated with telomere length and blood counts, suggesting an association with marrow function. In aggregate, these findings suggest a pro-inflammatory profile in TBDs. Our data provide new details on how TBD affects immune cells, particularly lymphocytes, which may contribute to the clinical phenotypes.

DOI: https://doi.org/10.1182/bloodadvances.2025015976

bioRxiv. 2025 Jun 26. pii: 2025.06.23.660389. [Epub ahead of print]

Synaptotagmin 1 and Synaptotagmin 7 promote MR1-mediated presentation of Mycobacterium tuberculosis antigens.

Se-Jin Kim, Jessie C Peterson, Andrew J Olive, Fikadu G Tafesse, Corinna A Kulicke, Elham Karamooz, David M Lewinsohn.

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that can be sensed by T cells, which are essential for the control of infection. In comparison to viral infections, Mtb antigens are relatively rare and hence, challenging to sample. Specialized antigen presentation pathways enable the presentation of such scarce antigens to CD8 + T cells, which are, thus, uniquely poised to survey intracellular environments. A subset of CD8 + T cells prevalent in the airways, known as mucosal associated invariant T (MAIT) cells, can be activated through the presentation of Mtb antigens via the MHC class I-related protein 1 (MR1) molecule. Prior work demonstrates that endosomal calcium signaling is critical for MR1-mediated presentation of Mtb-derived antigens. Here, we show that the calcium-sensing trafficking proteins Synaptotagmin (Syt) 1 and Syt7 specifically promote MAIT cell activation in response to Mtb-infected cells. In bronchial epithelial cells, Syt1 and Syt7 localize to late endo-lysosomes and MR1 vesicles. Loss of Syt1 and Syt7 results in enlarged MR1 vesicles and an increased number of MR1 vesicles in close proximity to Mtb-containing vacuoles during infection. This study identifies a novel pathway in which Syt1 and Syt7 facilitate the translocation of MR1 from Mtb-containing vacuoles, potentially to the cell surface for antigen presentation.

DOI: https://doi.org/10.1101/2025.06.23.660389

Front Immunol. 2025 ;16 1601223

Longitudinal immune profiling following autologous hematopoietic stem cell transplantation in multiple sclerosis: insights into immune reconstitution and disease modulation.

Malin Müller, Ivan Pavlovic, Anna Wiberg, Joachim Burman.

Introduction: Autologous hematopoietic stem cell transplantation (AHSCT) is an effective treatment for relapsing remitting multiple sclerosis, yet the mechanisms underlying immune reset and sustained remission remain incompletely understood. This study provides a longitudinal immune profiling of patients undergoing AHSCT, with a specific focus on immune reconstitution at two years post-AHSCT.
Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 22 relapsing-remitting multiple sclerosis patients at baseline and multiple time points post-AHSCT. Immune reconstitution was characterized using high-dimensional mass cytometry (CyTOF) and flow cytometry to assess phenotypic changes in B cells, T cells, and myeloid cells.
Results: AHSCT led to profound alterations in immune cell populations. B-cell recovery was marked by a rapid expansion of naïve B cells, while memory B cells and plasmablasts remained depleted. Notably, patients with evidence of inflammatory disease activity (EIDA) post-AHSCT exhibited higher pre-transplant frequencies of non-switched IgD+IgM+ memory B cells, raising the possibility of a potential biomarker for treatment response. Myeloid-cell reconstitution showed a decline in classical monocytes and an increase in non-classical monocytes and plasmacytoid dendritic cells, potentially shifting the immune balance toward a more tolerogenic state. CD4 T-cell reconstitution demonstrated a shift from central memory (Tcm) to effector memory (Tem) phenotypes, with a selective depletion of polyfunctional Th1/Th17cells lacking PD-1 expression. Clusters enriched for PD-1+ Tem CD4 T cells appeared to differ between patients with and without EIDA. Furthermore, an increase in atypical naïve CCR7⁻CD62L⁻ CD4 T cells was observed in EIDA patients, raising questions about their role in the pathophysiology of MS. CD8 T-cell reconstitution followed a similar pattern, with a shift from a naïve/Tcm-dominant to a Tem-skewed population, albeit with substantial interpatient variability. Mucosal-associated invariant T cells (MAIT) cells showed a sustained decrease, possibly reflecting microbiota alterations post-transplant.
Conclusions: Taken together, these findings provide an exploratory characterization of immune reconstitution following AHSCT, highlighting candidate biomarkers and mechanisms that warrant validation in larger cohorts to guide patient stratification and monitor treatment responses in multiple sclerosis.

Keywords: autologous hematopoietic stem cell transplantation (AHSCT); flow cytometry; immune reconstitution; mass cytometry; multiple sclerosis (MS); neuroimmunology

DOI: https://doi.org/10.3389/fimmu.2025.1601223