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Due to changes in global climate, the geographic distribution of ticks and tick-borne infections is increasing and represents a growing global health concern for humans. Ticks of the genus Ixodidae are globally abundant and transmit a wide variety of pathogens that cause human infections, including tick-borne encephalitis and Lyme borreliosis. The transmission of pathogens into human skin while blood feeding causes changes in the local immune cell network and has various effects on structural skin cells, including sensory neurons. Recent studies have focused on the effect of tick saliva on cells at the cutaneous tick-host interface and have suggested a strong immunomodulatory function. Within seconds after a tick bite, saliva containing various bioactive molecules is secreted into the host’s skin, leading to vasodilation, inhibition of coagulation and anti-inflammatory actions. Inhibition of immune cell recruitment and cytokine secretion, facilitate prolonged tick attachment and blood feeding as well as pathogen transmission. Therefore, in recent years, efforts have intensified to identify tick salivary compounds by multi-omics approaches and investigate their individual effects on innate and adaptive immunological mechanisms. In this review, we summarize important features of tick saliva molecules and how they influence and modulate skin cell behavior on the tick-host interface to facilitate tick attachment and pathogen transmission. Further, we highlight immunomodulatory mechanisms of salivary compounds and their potential role as novel treatment agents for inflammatory skin diseases and in tick vaccine development.

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. Arthropod vectors induce physiological and immunological changes during ectoparasitic feeding, and Langerhans cells are key immune sentinels in the epidermal barrier. Here, the authors show that tick feeding reprograms Langerhans cells to promote tolerance and weaken T cell responses during pathogen transmission.

During cutaneous tick attachment, the feeding cavity becomes a site of transmission for tick salivary compounds and tick-borne pathogens. However, the immunological consequences of tick feeding for human skin remain unclear. Here, we assessed human skin and blood samples upon tick bite and developed a human skin explant model mimicking Ixodes ricinus bites and tick-borne pathogen infection. Following tick attachment, we observed rapidly occurring patterns of immunomodulation, including increases in neutrophils and cutaneous B and T cells. T cells upregulated tissue residency markers, while lymphocytic cytokine production was impaired. In early stages of Borrelia burgdorferi model infections, we detected strain-specific immune responses and close spatial relationships between macrophages and spirochetes. Preincubation of spirochetes with tick salivary gland extracts hampered accumulation of immune cells and increased spirochete loads. Collectively, we showed that tick feeding exerts profound changes on the skin immune network that interfere with the primary response against tick-borne pathogens.

Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes.

BackgroundTumor-associated macrophages (TAM) constitute the most abundant immune cells in the tumor stroma initiating pro-inflammatory (M1) or immunosuppressive (M2) responses depending on their polarization status. Advances in tumor immunotherapy call for a detailed understanding of potential immunogenic mechanisms of irradiation routinely applied in rectal cancer patients.MethodsTo test the effects of radiotherapy on TAM, we ex vivo irradiated tissue samples of human rectal cancer and assessed the phenotype by flow cytometry. We furthermore evaluated the distribution of leucocyte subsets in tissue sections of patients after short-course radiotherapy and compared findings to non-pretreated rectal cancer using an immunostaining approach. Organotypic assays (OTA) consisting of macrophages, cancer-associated fibroblast and cancer cell lines were used to dissect the immunological consequences of irradiation in macrophages.ResultsWe demonstrate that short-course neoadjuvant radiotherapy in rectal cancer patients is associated with a shift in the polarization of TAM towards an M1-like pro-inflammatory phenotype. In addition, ex vivo irradiation caused an increase in the phagocytic activity and enhanced expression of markers associated with stimulatory signals necessary for T-cell activation. In OTA we observed that this alteration in macrophage polarization could be mediated by extracellular vesicles (EV) derived from irradiated tumor cells. We identified high mobility group box 1 in EV from irradiated tumor cells as a potential effector signal in that crosstalk.ConclusionsOur findings highlight macrophages as potential effector cells upon irradiation in rectal cancer by diminishing their immunosuppressive phenotype and activate pro-inflammation. Our data indicate that clinically applied short-term radiotherapy for rectal cancer may be exploited to stimulate immunogenic macrophages and suggest to target the polarization status of macrophages to enhance future immunotherapeutic strategies.

Background 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. Methods 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. Results 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. Conclusions 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.

Cutaneous T cell lymphoma is a rare, difficult to diagnose malignancy of T cells. Malignant T cells, together with populations of stromal cells and B cells, shape their own tumor niche for improved cancer cell survival in the skin.

Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.

Patients with polymorphic light eruption (PLE) develop lesions upon the first exposure to sun in spring/summer, but lesions usually subside during season due to the natural (or medical) photohardening. However, these lesions tend to reappear the following year and continue to do so in most patients, suggesting the presence of a disease memory. To study the potential role of skin resident memory T cells (Trm), we investigated the functional phenotype of Trm and the expression of IL-15 in PLE. IL-15 is known to drive Trm proliferation and survival. Multiplex immunofluorescence was used to quantify the expression of CD3, CD4, CD8, CD69, CD103, CD49a, CD11b, CD11c, CD68, granzyme B (GzmB), interferon-gamma (IFN-γ), and IL-15 in formalin-fixed, paraffin-embedded lesional skin samples from PLE patients and healthy skin from control subjects. Unlike the constitutive T cell population in healthy skin, a massive infiltration of T cells in the dermis and epidermis was observed in PLE, and the majority of these belonged to CD8 + T cells which express Trm markers (CD69, CD103, CD49a) and produced cytotoxic effector molecules GzmB and IFN-γ. Higher numbers of CD3 + T cells and CD11b + CD68 + macrophages produced IL-15 in the dermis as compared to healthy skin. The dominant accumulation of cytotoxic Trm cells and increased expression of IL-15 in lesional skin of PLE patients strongly indicates the potential role of skin Trm cells in the disease manifestation and recurrence.

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