BACKGROUND:Durable protection against viral infections relies on tissue-resident memory T (TRM) cells at pathogen entry sites. The oral cavity is a critical mucosal barrier frequently exposed to viral pathogens; however, the phenotypic characteristics and spatial organization of virus-specific T cells in the human oral mucosa remain poorly understood. OBJECTIVE:This study aimed to define how virus-specific T cells maintain long-term residency in the oral mucosa and to identify cellular interactions supporting their persistence. METHODS:We profiled predicted virus-specific T cells in the blood and oral mucosa of seven healthy individuals who recently recovered from SARS-CoV-2 infection. Single-cell RNA and T cell receptor sequencing, spatial transcriptomics, and immunofluorescence (IF) were used to define cell composition, localization, and interactions. RESULTS:Cytomegalovirus-specific T cells were predominantly CD4+ effector memory T cells, whereas Epstein-Barr virus- and SARS-CoV-2-specific T cells were mainly CD8+ TRM cells with cytotoxic features. Cell-cell communication analysis suggested that predicted virus-specific CD8+ TRM cells were embedded in highly interactive signaling networks, receiving strong inputs from fibroblasts and dendritic cells. Spatial transcriptomics and IF confirmed close associations between CD8+ TRM, fibroblasts, and dendritic cells. CONCLUSION:Predicted virus-specific CD8+ TRM cells appear to play a prominent role in the human oral mucosa, where supportive communication networks with fibroblasts and dendritic cells likely contribute to their persistence and long-term survival at this critical barrier site.

Background A subset of patients with a bleeding tendency undergoing hemostatic evaluation may be misdiagnosed as bleeding disorder of unknown cause (BDUC). Key Clinical Question Should vitamin C deficiency be considered in patients with bleeding symptoms but normal hemostatic test results suggestive of BDUC? Clinical Approach We report on a patient with bleeding symptoms despite normal hemostatic examination, in whom vitamin C deficiency was ultimately identified as the cause of the bleeding disorder. The patient, a 26-year-old man, presented with extensive ecchymoses, anemia and sclerodermatous skin changes of the left leg. His nutritional anamnesis revealed markedly restricted eating habits. Vitamin C supplementation led to normalization of hemoglobin levels and marked improvement of the sclerodermatous skin changes. Conclusion This case demonstrates that vitamin C deficiency can mimic hematologic and dermatologic disorders and highlights the importance of considering nutritional deficiencies as potential causes of bleeding, even in high-income countries.

Abstract Inflammatory skin diseases (ISDs) affect up to 25% of the global population. Yet, large-scale comparative single-cell RNA-sequencing (scRNA-seq) analyses between ISDs are still missing. Here, we integrated scRNA-seq datasets spanning 27 skin diseases from 50 studies, comprising over 2 million cells from 441 samples. Using the healthy skin cell atlas as reference, we could build a robust ISD atlas that enabled us to differentiate universal inflammatory signatures and disease-specific ones. This highlighted, for example, a shared gene program between keratinocytes in atopic dermatitis and parapsoriasis, not present in cutaneous T-cell lymphoma, confirms the plasticity of Th17 cells throughout ISDs, defines specific macrophage signatures in acne, and reveals a yet undescribed role of mural cells in ISDs. This demonstrates the power of the ISD atlas as a resource to resolve disease-specific immune mechanisms. The complete atlas is available through an interactive online portal at https://isd-atlas.derma.meduniwien.ac.at .

Oral mucositis (OM) is a severe adverse effect of conditioning treatments preceding allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the high incidence of OM in transplant recipients, there is a lack of effective strategies for risk assessment. The aim of this study was to identify risk factors for OM development and evaluate the significance of oral health prior to allo-HSCT. A retrospective analysis of 242 adult patients receiving allo-HSCT was conducted, grading OM occurrence and severity using the World Health Organization scale. Furthermore, a radiographic assessment score was introduced to measure dental damage and restoration status in patients undergoing HSCT. In this cohort, 51.24% of patients developed clinically significant OM, with a mean grade of 1.1 (±1.3 standard deviation). Additionally, OM severity correlated with the total body irradiation dose (P < 0.0001). Among the 61 patients evaluated for dental treatment before HSCT, a significantly higher proportion developed OM (93.2%; P < 0.0001). Moreover, we observed that higher pretransplant dental damage was associated with more severe OM (P = 0.039). These findings provide a rationale for a detailed pretransplant dental examination to assess OM risk in HSCT recipients.

Adaptor proteins associated with the T cell receptor (TCR) play critical roles in regulating immune responses by Translating receptor engagement into intracellular signals. T cell Receptor Associated Transmembrane Adaptor 1 (TRAT1) has been implicated in modulating TCR complex stability, but its functional role in human effector and regulatory CD4⁺ T cell subsets remains poorly understood. This study aimed to elucidate the role of TRAT1 in regulating T cell activation and differentiation, particularly in helper T cells function and regulatory T cells. Primary human CD4⁺ T cells, including thymus-derived and induced regulatory T cells (Treg), were genetically modified by CRISPR/Cas9-mediated gene deletion or retro-/lentiviral overexpression of TRAT1. Functional assays, flow cytometry, cytokine quantification, and RNA sequencing were performed to evaluate modulation of T cell functions. Mechanistic studies included pathway inhibition using small molecules and phospho-protein analysis. The influence of TRAT1 on Treg function was further assessed in a CAR Treg context in an immune organoid model of allo-rejection. Thymus-derived, TGFb-induced and FOXP3-transgenic Treg displayed reduced expression of TRAT1 compared to effector T cells, which showed pronounced up-regulation of TRAT1 following activation. In effector T cells, deletion of TRAT1 led to increased signaling through the phosphoinositide 3-kinase pathway resulting in enhanced proliferation and increased expression of activation markers. However, this was accompanied by reduced production of interleukin-17, which was linked to elevated activity of STAT6 as shown by inhibition experiments using small molecule inhibitors. Overexpression and CRISPR/Cas9-mediated knockout of TRAT1 in Treg enhanced suppression of CD4⁺ target cells via up-regulation of LAP/GARP but reduced suppression of CD8⁺ target cells, an effect confirmed in HLA-A2-specific CAR Treg in a human organoid model of allo-rejection. TRAT1 acts as a dual regulator of human CD4⁺ T cell function, limiting effector activation through modulation of intracellular signaling and supporting regulatory T cell-mediated suppression. These findings reveal a novel mechanism of immune regulation with potential implications for the development of cell-based immunotherapies.

Arthropods are ancient vectors of infectious disease that alter the immune environment of the skin during feeding. The epidermis and its immune sentinels, including Langerhans cells, are critical for protection against ectoparasitic arthropods such as ticks. Here, we investigate how human Langerhans cells respond to clinical and experimental tick bites and concomitant infection with the tick-borne bacterium Borrelia burgdorferi. Using imaging, migration assays, immune spheroid models, and single-cell transcriptomic analysis of patient samples, we show that tick bites and tick saliva reprogram Langerhans cells to increase migration into lymphatic tissues, adopt a tolerogenic state marked by specific transcriptional programs, reduced ability to induce pro-inflammatory helper T cells, and enhanced promotion of type 2 and regulatory T cell responses. This shift dampens protective immunity and helps explain how ticks and their pathogens evade host defense and achieve efficient transmission.

Objective: Classical follicular lymphoma (FL) is a heterogeneous malignancy. Early progression within 24 months (POD24) is linked to poor outcomes. However, precise risk stratification remains unclear. We aimed to explore chemokine receptor (CR) expression profiles as potential markers of disease biology and outcome in FL. Methods: We analyzed mRNA expression of CCR1-CCR10, CXCR1-CXCR5, CX3CR1, and XCR1 in 52 FL samples (13 POD24, 39 non-POD24) using RT-qPCR. Immunohistochemistry for CCR3, CCR7, CXCR3, CXCR4, and CXCR5 was performed. Reactive tonsils (n = 5) served as controls. Results: Compared to controls, FL samples showed lower CCR1, CCR6, CCR7, CXCR1, CXCR5, and CX3CR1 but higher CCR4, CCR5, CCR8, and CCR9 expression. Grade 3a FL correlated with reduced CCR8, CXCR1, and CXCR3, and increased CCR7. POD24 cases had elevated CCR3, CCR4, CCR7, CXCR4, and XCR1 but reduced CXCR3. High CCR3, CCR4, and CCR10 levels were linked to inferior survival. Cluster analysis revealed two CR-based subgroups; most POD24 cases clustered in the group with worse prognosis. Conclusion: These findings suggest distinct chemokine receptor expression profiles contribute to FL progression. Our data highlight several CRs as candidate prognostic markers and potential therapeutic targets in the context of POD24, warranting further investigation in larger, prospective cohorts. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Results of the Wilcoxon rank sum tests, dependent variable = first component of the PCA.

BACKGROUND Graft-versus-host disease (GvHD) is a major life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT), limiting the broad application of HSCT for haematological malignancies. Cutaneous GvHD is described as a post-transplant inflammatory reaction by skin-infiltrating donor T cells and remaining recipient tissue-resident memory T cells. Despite the major influence of lymphocytes on GvHD pathogenesis, the complex role of mononuclear phagocytes (MNPs) in tissues affected by GvHD is increasingly appreciated. OBJECTIVES To characterize the identity, origin and functions of MNPs in patients with acute cutaneous GvHD. METHODS Using single-cell RNA sequencing and multiplex tissue immunofluorescence, we identified an increased abundance of MNPs in skin and blood from 36 patients with acute cutaneous GvHD. In cases of sex-mismatched transplantation, we used expression of X-linked genes to detect rapid tissue adaptation of newly recruited donor MNPs resulting in similar transcriptional states of host- and donor-derived macrophages within GvHD skin lesions. RESULTS We showed that cutaneous GvHD lesions harbour expanded CD163+ tissue-resident macrophage populations with anti-inflammatory and tissue-remodelling properties including interleukin-10 cytokine production. Cell-cell interaction analyses revealed putative signalling to strengthen regulatory T-cell responses. Notably, macrophage polarization in chronic cutaneous GvHD types was proinflammatory and drastically differed from acute GvHD, supporting the notion of distinct cellular players in different clinical GvHD subtypes. CONCLUSIONS Overall, our data reveal a surprisingly dynamic role of MNPs after HSCT. Specific and time-resolved targeting to repolarize this cell subset may present a promising therapeutic strategy in combatting GvHD skin inflammation.