Efficient homing of T cells via afferent lymphatics requires mechanical arrest and integrin-supported chemokine guidance

Abstract

Little is known regarding lymph node (LN)-homing of immune cells via afferent lymphatics. Here, we show, using a photo-convertible Dendra-2 reporter, that recently activated CD4 T cells enter downstream LNs via afferent lymphatics at high frequencies. Intra-lymphatic immune cell transfer and live imaging data further show that activated T cells come to an instantaneous arrest mediated passively by the mechanical 3D-sieve barrier of the LN subcapsular sinus (SCS). Arrested T cells subsequently migrate randomly on the sinus floor independent of both chemokines and integrins. However, chemokine receptors are imperative for guiding cells out of the SCS, and for their subsequent directional translocation towards the T cell zone. By contrast, integrins are dispensable for LN homing, yet still contribute by increasing the dwell time within the SCS and by potentially enhancing T cell sensing of chemokine gradients. Together, these findings provide fundamental insights into mechanisms that control homing of lymph-derived immune cells.

Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

“…In accordance with our MS data, dysfunctions in glutamate recycling processes were implicated in AD and drastic declines in the excitatory amino acid transporter 1 (EAAT1) of astrocytes within human tissue and astrocytic cultures exposed to Aβ oligomers have been reported (Huang et al, 2018;Zoia et al, 2004). Interestingly, GS immunoreactive area adjacent to plaques tightly associated with post-synaptic density, suggesting that restoration of GS expression to homeostatic WT levels in Aβ- Our quantitative MS analysis also showed that both retinal and cerebral tissues in old ADtg mice displayed significant up-regulation of several inflammatory-related proteins such as ICAM1, an adhesion molecule found on antigen-presenting cells and pericytes which facilitates transport of innate immune cells across the BBB (Martens et al, 2020;Proebstl et al, 2012). These findings are in line with previous studies reporting up-regulation of cerebral ICAM1 in a number of AD transgenic models (Ferretti et al, 2016) and, moreover, correlations with Aβ and tau pathology in human AD patients (Walker et al, 2017).…”

Lymphatic PD-L1 expression restricts tumor-specific CD8+ T cell responses

“…Additionally, PD-L1 expression is constitutively high in LN LECs 6 , both in cells lining the floor of the subcapsular sinus and the medullary sinuses 5,36 . PD-L1 expressed by both subcapsular sinus and medullary sinus LECs could equally affect T cells recirculating from upstream tissues and entering the LN via afferent lymphatics 37,38 . Additionally, medullary LEC-expressed PD-L1 could interact with PD-1 + T cells exiting the LN via efferent lymphatics.…”

“…Additionally, PD-L1 expression is constitutively high in LN LECs (Tewalt et al, 2012), both in cells lining the floor of the subcapsular sinus and the medullary sinuses (Cohen et al, 2014, Fujimoto et al, 2020. PD-L1 expressed by either of these LEC subsets could again affect recirculating T cells that enter the LN via afferent lymphatics (Braun et al, 2011, Martens et al, 2020. Additionally, medullary LEC-expressed PD-L1 might interact with PD-1 + T cells exiting the LN via efferent lymphatics, such as CM T cells that previously entered the LN via the blood circulation and freshly primed T cells, which are sensitive to PD-L1 / PD-1 inhibition (Ahn et al, 2018).…”

Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs

“…In inflammatory and infectious diseases, the lymphatic network must manage the fluid balance during inflammatory swelling. Perhaps more importantly, there is increasing evidence that both innate and adaptive immunological responses are crucially dependent on the lymphatics during all stages of an immune response [ 113 , 114 ]. Thus, the activation of VEGF-C could be used as a generic means to boost any immune response like an adjuvant.…”