Lymphatic Migration of Immune Cells.

Lymphatic vessels collect interstitial fluid that has extravasated from blood vessels and return it to the circulatory system. Another important function of the lymphatic network is to facilitate immune cell migration and antigen transport from the periphery to draining lymph nodes. This migration plays a crucial role in immune surveillance, initiation of immune responses and tolerance. Here we discuss the significance and mechanisms of lymphatic migration of innate and adaptive immune cells in homeostasis, inflammation and cancer

Lymphatic Migration of Immune Cells

Lymphatic vessels collect interstitial fluid that has extravasated from blood vessels and return it to the circulatory system. Another important function of the lymphatic network is to facilitate immune cell migration and antigen transport from the periphery to draining lymph nodes. This migration plays a crucial role in immune surveillance, initiation of immune responses and tolerance. Here we discuss the significance and mechanisms of lymphatic migration of innate and adaptive immune cells in homeostasis, inflammation and cancer

Early growth response genes 2 and 3 regulate the expression of Bcl6 and differentiation of T follicular helper cells

T follicular helper (Tfh) cells support differentiation of B cells to plasma cells and high affinity antibody production in germinal centers (GC) and Tfh differentiation requires the function of B cell lymphoma 6 (Bcl6). We have now discovered that early growth response gene (Egr) 2 and 3 directly regulate the expression of Bcl6 in Tfh cells which is required for their function in regulation of GC formation. In the absence of Egr2 and 3, the expression of Bcl6 in Tfh cells is defective leading to impaired differentiation of Tfh cells resulting in a failure to form GCs following virus infection and defects in production of anti-viral antibodies. Enforced expression of Bcl6 in Egr2/3 deficient CD4 T cells partially restored Tfh differentiation and GC formation in response to virus infection. Our findings demonstrate a novel function of Egr2/3 which is important for Tfh cell development and Tfh cell mediated B cell immune responses.This work was supported by Arthritis Research UK. The authors declare that they have no conflicts of interest with the contents of this article

The Ins and Outs of Chemokine-Mediated Immune Cell Trafficking in Skin Cancer

Recent studies of the patterns of chemokine-mediated immune cell recruitment into solid tumors have enhanced our understanding of the role played by various immune cell subsets both in amplifying and inhibiting tumor cell growth and spread. Here we discuss how the chemokine/chemokine receptor networks bring together immune cells within the microenvironment of skin tumors, particularly melanomas, including their effect on disease progression, prognosis and therapeutic options

Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity

Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Neutrophils under the microscope: neutrophil dynamics in infection, inflammation, and cancer revealed using intravital imaging

Neutrophils rapidly respond to inflammation resulting from infection, injury, and cancer. Intravital microscopy (IVM) has significantly advanced our understanding of neutrophil behavior, enabling real-time visualization of their migration, interactions with pathogens, and coordination of immune responses. This review delves into the insights provided by IVM studies on neutrophil dynamics in various inflammatory contexts. We also examine the dual role of neutrophils in tumor microenvironments, where they can either facilitate or hinder cancer progression. Finally, we highlight how computational modeling techniques, especially agent-based modeling, complement experimental data by elucidating neutrophil kinetics at the level of individual cells as well as their collective behavior. Understanding the role of neutrophils in health and disease is essential for developing new strategies for combating infection, inflammation and cancer

Leukocyte Motility Models Assessed through Simulation and Multi-objective Optimization-Based Model Selection

The advent of two-photon microscopy now reveals unprecedented, detailed spatio-temporal data on cellular motility and interactions in vivo. Understanding cellular motility patterns is key to gaining insight into the development and possible manipulation of the immune response. Computational simulation has become an established technique for understanding immune processes and evaluating hypotheses in the context of experimental data, and there is clear scope to integrate microscopy-informed motility dynamics. However, determining which motility model best reflects in vivo motility is non-trivial: 3D motility is an intricate process requiring several metrics to characterize. This complicates model selection and parameterization, which must be performed against several metrics simultaneously. Here we evaluate Brownian motion, Lévy walk and several correlated random walks(CRWs) against the motility dynamics of neutrophils and lymph node T cells under inflammatory conditions by simultaneously considering cellular translational and turn speeds, and meandering indices. Heterogeneous cells exhibiting a continuum of inherent translational speeds and directionalities comprise both datasets, a feature significantly improving capture of in vivo motility when simulated as a CRW. Furthermore, translational and turn speeds are inversely correlated, and the corresponding CRW simulation again improves capture of our in vivo data, albeit to a lesser extent. In contrast, Brownian motion poorly reflects our data. Lévy walk is competitive in capturing some aspects of neutrophil motility, but T cell directional persistence only, therein highlighting the importance of evaluating models against several motility metrics simultaneously. This we achieve through novel application of multi-objective optimization, wherein each model is independently implemented and then parameterized to identify optimal trade-offs in performance against each metric. The resultant Pareto fronts of optimal solutions are directly contrasted to identify models best capturing in vivo dynamics, a technique that can aid model selection more generally. Our technique robustly determines our cell populations’ motility strategies, and paves the way for simulations that incorporate accurate immune cell motility dynamics

Parasitized natural killer cells do not facilitate the spread of toxoplasma gondii to the brain.

Toxoplasmagondii is a protozoan parasite capable of invading immune cells and co-opting their migratory pathways to disseminate through the host. Natural Killer (NK) cells can be directly invaded by the parasite and this invasion alters NK cell migration, producing a hypermotile phenotype. However, the consequences of this hypermotile phenotype for the dissemination of T.gondii to the brain remain unknown. To address this, C57BL6/J mice were infected with freshly egressed tachyzoites (type IIPrugniaud strain) or with parasitized NK cells. Under both conditions, parasite loads in the brain were comparable, indicating that parasitized NK cells were not able to facilitate spread of T.gondii to the brain. Consistent with this, we found no evidence for the recruitment of endogenous NK cells to the brain at early time points post-infection, nor any changes in the expression of α4β1 integrin, involved in recruitment of NK cells to the brain. We therefore found no evidence for a role for hypermotile NK cells in delivery of parasites to the brain during acute infection with T.gondii