Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Self-peptide-dependent autoproliferation (AP) of B and T cells is a key mechanism in MS. Here, we show that pro-inflammatory B-T cell-enriched cell clusters (BTECs) form during AP and mirror features of a germinal center reaction. T-bet+CXCR3+ B cells are the main cell subset amplifying and sustaining their counterpart Th1 cells via interferon (IFN)-γ and are present in highly inflamed meningeal tissue. The underlying B cell activation signature is reflected by epigenetic modifications and receptor-ligand interactions with self-reactive T cells. AP+ CXCR3+ B cells show marked clonal evolution from memory to somatically hypermutated plasmablasts and upregulation of IFN-γ-related genes. Our data underscore a key role of T-bet+CXCR3+ B cells in the pathogenesis of MS in both the peripheral immune system and the CNS compartment, and thus they appear to be involved in both early relapsing-remitting disease and the chronic stage.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

Leptospirosis is a globally neglected re-emerging zoonosis affecting all mammals, albeit with variable outcomes. Humans are susceptible to leptospirosis; infection with Leptospira interrogans species can cause severe disease in humans, with multi-organ failure, mainly affecting kidney, lung and liver function, leading to death in 10% of cases. Mice and rats are more resistant to acute disease and can carry leptospires asymptomatically in the kidneys and act as reservoirs, shedding leptospires into the environment. The incidence of leptospirosis is higher in tropical countries, and countries with poor sanitation, where heavy rainfall and flooding favour infection. Diagnosis of leptospirosis is difficult because of the many different serovars and the variety of clinical symptoms that can be confused with viral infections. The physiopathology is poorly understood, and leptospirosis is often regarded as an inflammatory disease, like sepsis.
To investigate the causes of death in lethal leptospirosis, we compared intraperitoneal infection of male and female C57BL6/J mice with 108Leptospira of two strains of pathogenic L. interrogans. One strain, L. interrogans Manilae L495, killed the mice 4 days after infection, whereas the other strain, L. interrogans Icterohaemorrhagiae Verdun, did not induce any major symptoms in the mice. On day 3 post infection, the mice were humanely euthanised and blood and organs were collected. Bacterial load, biochemical parameters, cytokine production and leucocyte population were assessed by qPCR, ELISA, cytometry and immunohistochemistry.
Neither lung, liver, pancreas or kidney damage nor massive necroptosis or cytokine storm could explain the lethality. Although we did not find pro-inflammatory cytokines, we did find elevated levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES in the serum and organs of Leptospira-infected mice. In contrast, severe leptospirosis was associated with neutrophilia and vascular permeability, unexpectedly due to neutrophils and not only due to Leptospira infection. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.
Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed, in particular a lack of cytokine storm in acute leptospirosis. The fact that IL-10 was increased in infected mice may explain the lack of pro-inflammatory cytokines, emphasising the covert nature of Leptospira infections. Neutrophilia is a hallmark of human leptospirosis. Our findings confirm the ineffective control of infection by neutrophils and highlight their deleterious role in vascular permeability, previously only attributed to the ability of leptospires to damage and cross endothelial junctions. Finally, the identification of death due to myocarditis rather than kidney, liver or liver failure may reflect an overlooked but common symptom associated with poor prognosis in human leptospirosis. These features of neutrophilia and myocarditis are also seen in patients, making this mouse model a paradigm for better understanding human leptospirosis and designing new therapeutic strategies.
The Boneca laboratory was supported by the following programmes: Investissement d'Avenir program, Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" (ANR-10-LABX-62-IBEID) and by R&D grants from Danone and MEIJI. CW received an ICRAD/ANR grant (S-CR23012-ANR 22 ICRD 0004 01). SP received a scholarship by Université Paris Cité (formerly Université Paris V - Descartes) through Doctoral School BioSPC (ED562, BioSPC). SP has additionally received a scholarship "Fin de Thèse de Science" number FDT202404018322 granted by "Fondation pour la Recherche Médicale (FRM)". The funders had no implication in the design, analysis and reporting of the study.
Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

T helper (Th) cell subsets primarily assist B cells in differentiating into plasma cells in the germinal center. The mechanism of malignant transformation of plasma cells is an important target for the clinical treatment of MM; however, the mechanism remains unclear.
We collected the peripheral blood (PB) and bone marrow (BM) samples of 33 patients with MM. In addition, the PB was also collected from 25 normal healthy controls (HCs). We analyzed the percentages of Th cell subsets in the PB and BM samples of patients with MM.
Tfh/CD4+ were positively correlated with the proportion of myeloma cells in the BM and PB samples (r = 0.592, P = 0.002 and r = 0.510, P = 0.010 respectively), and showed a strong correlation between the BM and PB samples (r = 0.6559, P = 0.0095). In the PB samples, the percentages of Th2/CD4+ and Tfh2/Tfh cells were significantly lower in patients with MM than in HCs (P = 0.00013 and P = 0.0004, respectively), whereas the percentage of Th17/CD4+ and Tfh17/Tfh was significantly higher in newly diagnosed patients with MM than in HCs (P = 0.0037 and P = 0.03, respectively), and all these cells showed a good predictive value for MM (area under the curve [AUC] 0.781, = 0.792, = 0.837, and 0.723 respectively). In the PB samples, all subsets of PD-1+ICOS- Tfh showed a noticeable downward trend in MM from newly diagnosed to non-remission and remission groups. In contrast, all subsets of PD-1-ICOS+ Tfh increased gradually.
Th cell subsets play an important role in the occurrence and development of MM and may provide a fundamental basis for identifying new immunotherapy targets and prognosis.
Copyright © 2024 Zhang, Zhong, Fan, Mao and Li.

Viroimmunotherapy is evolving as a strong alternative for the standard treatment of malignant gliomas. Promising results from a recent clinical trial testing the anticancer effect of Delta-24-RGD in patients with glioblastoma suggested the induction of antitumoral immunity after viral administration. To further enhance the anti-glioma immune effect, we have armed Delta-24-RGD with the costimulatory ligand GITRL (Delta-24-GREAT [Glucocorticoid Receptor Enhanced Activity of T cells]).
We tested the infectivity and replication of Delta-24-GREAT, and the expression of ectopic GITRL in human and murine glioma cell lines. In vivo experiments involved the intracranial implantation of glioma cells into an immunocompetent model to study the anticancer effect, and rechallenging experiments to study long-term protection. Phenotypic and functional characterization of lymphocyte populations were performed by FACS and ELISA for Th1 cytokines expression, respectively.
Our results showed that Delta-24-GREAT infects and induces the expression of GITRL. Delta-24-GREAT prolonged the survival of glioma-bearing immunocompetent mice and resulted in both anti-viral and anti-glioma immune responses, including increased frequency of central memory CD8+ T cells. Rechallenging the surviving mice with a second implantation of glioma cells did not lead to tumor growth; however, the surviving mice developed lethal tumors when B16/F10 melanoma cells were implanted intracranially, strongly indicating that the immune response was specific for glioma antigens.
GITRL-armed Delta-24-RGD treatment results in an antigen-restricted antitumor memory, an enhanced anti-glioma effect, and the generation of central immune memory. Our results strongly indicate that this strategy represents a vertical advance in virotherapy designed to treat patients with malignant brain tumors.
© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2 cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. Here, we show that GITR, a member of the TNF superfamily, is expressed on both murine and human ILC2s. Strikingly, we demonstrate that GITR engagement of activated, but not naïve, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin- resistance. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.