quantifying-leukocyte-egress-via-lymphatic-vessels-from-murine-skin

Quantifying Leukocyte Egress via Lymphatic Vessels from Murine Skin and Tumors

Leukocyte egress from peripheral tissues to draining lymph nodes is not only critical for immune surveillance and initiation but also contributes to the ...

Oregon Health and Science University

Lymphatic vessels lie at the interface between peripheral sites of pathogen entry, adaptive immunity, and the systemic host. Though the paradigm is that their open structure allows for passive flow of infectious particles from peripheral tissues to lymphoid organs, virus applied to skin by scarification does not spread to draining lymph nodes. Using cutaneous infection by scarification, we analyzed the effect of viral infection on lymphatic transport and evaluated its role at the host-pathogen interface. We found that, in the absence of lymphatic vessels, canonical lymph-node-dependent immune induction was impaired, resulting in exacerbated pathology and compensatory, systemic priming. Furthermore, lymphatic vessels decouple fluid and cellular transport in an interferon-dependent manner, leading to viral sequestration while maintaining dendritic cell transport for immune induction. In conclusion, we found that lymphatic vessels balance immune activation and viral dissemination and act as an "innate-like" component of tissue host viral defense.

Lymphatic Vessels Balance Viral Dissemination and Immune Activation following Cutaneous Viral Infection.

Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8 T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8 T cell accumulation in tumor microenvironments. IFNγ produced by tissue-infiltrating, antigen-specific CD8 T cells, which are in close proximity to tumor-associated lymphatic vessels, is sufficient to induce lymphatic vessel PD-L1 expression. Disruption of IFNγ-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.

IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin.

In response to pathological challenge, the host generates rapid, protective adaptive immune responses while simultaneously maintaining tolerance to self and limiting immune pathology. Peripheral tissues (e.g., skin, gut, lung) are simultaneously the first site of pathogen-encounter and also the location of effector function, and mounting evidence indicates that tissues act as scaffolds to facilitate initiation, maintenance, and resolution of local responses. Just as both effector and memory T cells must adapt to their new interstitial environment upon infiltration, tissues are also remodeled in the context of acute inflammation and disease. In this review, we present the biochemical and biophysical mechanisms by which non-hematopoietic stromal cells and extracellular matrix molecules collaborate to regulate T cell behavior in peripheral tissue. Finally, we discuss how tissue remodeling in the context of tumor microenvironments impairs T cell accumulation and function contributing to immune escape and tumor progression.

Article	Year
Lymphatic Vessels Balance Viral Dissemination and Immune Activation following Cutaneous Viral Infection. Cell reports\| PubMed ID: 28954233	2017
IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin. The Journal of experimental medicine\| PubMed ID: 30381467	2018
Non-hematopoietic Control of Peripheral Tissue T Cell Responses: Implications for Solid Tumors. Frontiers in immunology\| PubMed ID: 30498499	2018

Ryan S. Lane

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