Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

Abstract

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

“…Nonetheless, there is ample evidence for immune cell autophagy-related genes dampening inflammation, including diminishing immune cell trafficking. In contrast, while emerging in vivo evidence links autophagy-related genes to a wide array of EC functions, including shear stress-induced homeostasis, angiogenesis, and thrombosis ( Sprott et al., 2019 ; Torisu et al., 2013 ; Vion et al., 2017 ; Verhoeven et al., 2021 ; Harlé et al., 2021 ), knowledge of EC autophagy as a regulator of inflammation is limited. Our findings demonstrated the occurrence and spatiotemporal regulation of autophagy (using GFP-LC3 puncta as readout) in acutely inflamed postcapillary venular ECs in vivo .…”

Expanded renal lymphatics improve recovery following kidney injury

“…Lymphatic vessels and LECs help to maintain tolerogenic cross‐presentation of self‐antigen and help to limit CD8+ T cell accumulation in the periphery (Hirosue et al, 2014 ; Lane et al, 2018 ). For example, disruption of LEC signaling to the immune environment increases pathogenic Th17 tissue infiltration and further propagates pro‐inflammatory conditions (Harle et al, 2021 ). In the present study, we tested how increased renal lymphatic density prior to the onset of AKI would impact renal outcomes and found that, while the acute response was largely unchanged, the hallmarks of CKD progression such as kidney function and fibrosis were improved.…”

Canonical and Non-Canonical Functions of the Autophagy Machinery in MHC Restricted Antigen Presentation

“…In addition to this role in central tolerance, endogenous antigen processing via macroautophagy might also be important for peripheral tolerance and regulatory CD4 + T cell stimulation. Along these lines lymphatic endothelial cells express MHC class II molecules to stimulate regulatory CD4 + T cells (33)(34)(35)(36). Autophagosomes fuse with MIICs in these cells (36).…”

“…Along these lines lymphatic endothelial cells express MHC class II molecules to stimulate regulatory CD4 + T cells (33)(34)(35)(36). Autophagosomes fuse with MIICs in these cells (36). Loss of ATG5 compromises regulatory T cell proliferation and phenotype, and results in exacerbated collagen induced arthritis with Th17 infiltrations (36).…”

“…Autophagosomes fuse with MIICs in these cells (36). Loss of ATG5 compromises regulatory T cell proliferation and phenotype, and results in exacerbated collagen induced arthritis with Th17 infiltrations (36). The macroautophagic machinery is then required in dendritic cells to maintain regulatory CD4 + T cell function (37).…”