Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration

Brinkman, C. Colin; Iwami, Daiki; Hritzo, Molly; Xiong, Yanbao; Ahmad, Sarwat; Thézenas, Simon; Hippen, Keli L.; Blazar, Bruce R.; Bromberg, Jonathan S.

doi:10.1038/ncomms12021

Cited by 59 publications

(97 citation statements)

References 52 publications

(75 reference statements)

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“…A recent study suggested a role for LEC-expressed VCAM-1 in homeostatic migration of nT reg but not of naïve CD4 + or CD8 + T cells from skin to the dLN (67). VCAM-1 is a known target of LTβR (136) and blockade of LTβR reduced nT reg exit from the skin (67).…”

Section: T Cell Entry and Migration Within Afferent Lvsmentioning

confidence: 99%

“…VCAM-1 is a known target of LTβR (136) and blockade of LTβR reduced nT reg exit from the skin (67). Similarly, fewer nT reg devoid of the LTβR ligand, LTα, exited from the skin (67).…”

Section: T Cell Entry and Migration Within Afferent Lvsmentioning

confidence: 99%

“…VCAM-1 is a known target of LTβR (136) and blockade of LTβR reduced nT reg exit from the skin (67). Similarly, fewer nT reg devoid of the LTβR ligand, LTα, exited from the skin (67). As with ICAM-1, VCAM-1 expression is induced on afferent LVs during inflammatory conditions (131, 132).…”

Section: T Cell Entry and Migration Within Afferent Lvsmentioning

confidence: 99%

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T Cell Trafficking through Lymphatic Vessels

2016

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T cell migration within and between peripheral tissues and secondary lymphoid organs is essential for proper functioning of adaptive immunity. While active T cell migration within a tissue is fairly slow, blood vessels and lymphatic vessels (LVs) serve as speedy highways that enable T cells to travel rapidly over long distances. The molecular and cellular mechanisms of T cell migration out of blood vessels have been intensively studied over the past 30 years. By contrast, less is known about T cell trafficking through the lymphatic vasculature. This migratory process occurs in one manner within lymph nodes (LNs), where recirculating T cells continuously exit into efferent lymphatics to return to the blood circulation. In another manner, T cell trafficking through lymphatics also occurs in peripheral tissues, where T cells exit the tissue by means of afferent lymphatics, to migrate to draining LNs and back into blood. In this review, we highlight how the anatomy of the lymphatic vasculature supports T cell trafficking and review current knowledge regarding the molecular and cellular requirements of T cell migration through LVs. Finally, we summarize and discuss recent insights regarding the presumed relevance of T cell trafficking through afferent lymphatics.

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Section: T Cell Entry and Migration Within Afferent Lvsmentioning

confidence: 99%

“…VCAM-1 is a known target of LTβR (136) and blockade of LTβR reduced nT reg exit from the skin (67). Similarly, fewer nT reg devoid of the LTβR ligand, LTα, exited from the skin (67).…”

Section: T Cell Entry and Migration Within Afferent Lvsmentioning

confidence: 99%

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T Cell Trafficking through Lymphatic Vessels

2016

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“…While a literature search to biologically explain each gene of the 32-gene signature was not part of the current study, one gene of that particularly struck interest was Lymphotoxin Beta (LTB), which was elevated in cluster1 patient tumor samples. Interestingly, LTB has been shown to specifically stimulate Tregs to migrate from the tissue to the lymph nodes via afferent lymphatics [37]. This therefore may at least partly attribute the positive clinical associations of cluster1 patients to elevated LTB expression, which may be directing immunosuppressive Tregs away from tumor tissue sites, thus unleashing the antitumor response within cluster1 tumor samples.…”

Section: Discussionmentioning

confidence: 99%

Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples

Givechian¹,

Wnuk²,

Garner³

et al. 2018

Preprint

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Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples AbstractImmune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of Regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n=135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.

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“…Importantly, T Reg cells as well as central memory T cells, but not effector memory or effector T cells, also maintain high levels of CCR7 expression and reside in the LN. When comparing cell populations in afferent vs. efferent lymph, the efferent was found to be mostly composed of T cells, with more CD4 + vs. CD8 + T cells [47,48], while afferent lymph consisted mostly of αβ T cells, efficient than CD8 + T cells at exiting peripheral tissue via afferent lymphatics [49][50][51][52], and of the T cells found in the afferent lymph, most are either memory or T Reg cells [50,[53][54][55][56]. However, some research has suggested that naïve T cells may use afferent lymphatics when migrating from peripheral tissues [51,[57][58][59][60].…”

Section: Lymphatic Transport Of Leukocytesmentioning

confidence: 99%

Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges

Maisel

Sasso

Potin

et al. 2017

Advanced Drug Delivery Reviews

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Lymphatic vessels are the primary route of communication from peripheral tissues to the immune system; as such, they represent an important component of local immunity. In addition to their transport functions, new immunomodulatory roles for lymphatic vessels and lymphatic endothelial cells have come to light in recent years, demonstrating that lymphatic vessels help shape immune responses in a variety of ways: promoting tolerance to self-antigens, archiving antigen for later presentation, dampening effector immune responses, and resolving inflammation, among others. In addition to these new biological insights, the growing field of immunoengineering has begun to explore therapeutic approaches to utilize or exploit the lymphatic system for immunotherapy.

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Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration

Cited by 59 publications

References 52 publications

T Cell Trafficking through Lymphatic Vessels

T Cell Trafficking through Lymphatic Vessels

Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples

Exploiting lymphatic vessels for immunomodulation: Rationale, opportunities, and challenges

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