Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. However, characterization of the immunological processes occurring in human pancreatic lymphatic tissues is lacking. Here, we conduct a comprehensive study of immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of non-diabetic control (ND), β cell autoantibody-positive non-diabetic (AAb+), and T1D donors using flow cytometry and CITEseq. Compared to ND pancreas-draining lymph nodes (pLN), AAb+ and T1D donor pLNs display decreased CD4+ Treg and increased stem-like CD8+ T cell signatures, while only T1D donor pLNs exhibit naive T cell and NK cell differentiation. Mesenteric LNs have modulations only in CD4+ Tregs and naive cells, while splenocytes lack these perturbations. Further, T cell expression of activation markers and IL7 receptor correlate with T1D genetic risk. These results demonstrate tissue-restricted immune changes occur before and after T1D onset.
© 2025. The Author(s).

Long coronavirus disease (COVID) is a heterogeneous clinical condition of uncertain etiology triggered by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we used ultrasensitive approaches to profile the immune system and the plasma proteome in healthy convalescent individuals and individuals with long COVID, spanning geographically independent cohorts from Sweden and the United Kingdom. Symptomatic disease was not consistently associated with quantitative differences in immune cell lineage composition or antiviral T cell immunity. Healthy convalescent individuals nonetheless exhibited higher titers of neutralizing antibodies against SARS-CoV-2 than individuals with long COVID, and extensive phenotypic analyses revealed a subtle increase in the expression of some co-inhibitory receptors, most notably PD-1 and TIM-3, among SARS-CoV-2 nonspike-specific CD8+ T cells in individuals with long COVID. We further identified a shared plasma biomarker signature of disease linking breathlessness with apoptotic inflammatory networks centered on various proteins, including CCL3, CD40, IKBKG, IL-18 and IRAK1, and dysregulated pathways associated with cell cycle progression, lung injury and platelet activation, which could potentially inform the diagnosis and treatment of long COVID.
© 2025. The Author(s).

Mucosal antigen-specific T cells are pivotal for pathogen clearance and immune modulation in respiratory infections. Dysregulated T cell responses exacerbate coronavirus disease 2019 severity, marked by cytokine storms and respiratory failure. Despite extensive description in peripheral blood, the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells in the lungs remain elusive. Here we conducted integrated single-cell profiling of SARS-CoV-2-specific T cells in 122 bronchoalveolar lavage fluid (BALF) and 280 blood samples from 159 patients, including 27 paired BALF and blood samples from 24 patients. SARS-CoV-2-specific T cells were robustly elicited in BALF irrespective of prior vaccination, correlating with diminished viral loads, lessened systemic inflammation and improved respiratory function. SARS-CoV-2-specific T cells in BALF exhibited profound activation, along with proliferative and multi-cytokine-producing capabilities and a glycolysis-driven metabolic signature, which were distinct from those observed in peripheral blood mononuclear cells. After viral clearance, these specific T cells maintained a polyfunctional tissue-resident memory phenotype, highlighting their critical roles in infection control and long-term protection.
© 2025. The Author(s).

Humanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined.
We established an autologous humanized mouse tumour model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumours generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumours after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.
We found human T cell subsets described in human cancer, including progenitor exhausted (Tpex), terminally exhausted (Tex-term) and tissue-resident (TRM) cells in tumour-bearing humanized mice with accumulation of Tex-term and TRM in the tumour. In addition, we identified tumour-reactive CD8+ T cells through expression of CD137. This subpopulation of de novo arising human CD137+ CD8+ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137+ CD8+ T cells exhibited tumour-specific clonal expansion and presented signature overlap with tumour-reactive CD8+ T cells described in human cancer. We demonstrate superior anticancer activity of this activated and exhausted-like human CD8+ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumours. Mice adoptively transferred with CD137+ CD8+ T cells showed reduced tumour growth and higher CD8+ T cell tumour infiltration, correlating with control of human tumours.
We established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8+ T cells with an activated and exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.
Swiss Cancer Research foundation.
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Cell directed therapy is an evolving therapeutic approach to treat organ dysfunction arising from hyperinflammation and cytokine storm by processing immune cells in an extracorporeal circuit. To investigate the mechanism of action of the Selective Cytopheretic Device (SCD), in vitro blood circuits were utilized to interrogate several aspects of the immunomodulatory therapy. SCD immunomodulatory activity is due to its effects on circulating neutrophils and monocytes in a low ionized calcium (iCa, Ca2+) blood circuit. Activated neutrophils adhere to the SCD fibers and degranulate with release of the constituents of their exocytotic vesicles. Adhered neutrophils in the low iCa environment display characteristics of apoptotic senescence. These neutrophils are subsequently released and returned back to circulation, demonstrating a clear potential for in vivo feedback. For monocytes, SCD treatment results in the selective adhesion of more pro-inflammatory subsets of the circulating monocyte pool, as demonstrated by both cell surface markers and cytokine secretory rates. Once bound, over time a subset of monocytes are released from the membrane with a less inflammatory functional phenotype. Similar methods to interrogate mechanism in vitro have been used to preliminarily confirm comparable findings in vivo. Therefore, the progressive amelioration of circulating leukocyte activation and immunomodulation of excessive inflammation observed in SCD clinical trials to date is likely due to this continuous autologous leukocyte processing.
© 2024. The Author(s).