Antigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown

Abstract

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8+ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8+ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8+ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8+ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8+ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8+ T cell entry into the CNS and triggers CD8+ T cell-mediated focal BBB breakdown.

Endothelial cells and macrophages as allies in the healthy and diseased brain

“…Since BBB endothelial cells are highly polarized, it cannot be taken for granted that they can also take up antigens from the abluminal and thus CNS facing side. However, two independent studies showed that BMECs can take up exogenous antigen from their abluminal side in vitro and in vivo , process and cross-present it on their luminal side in an MHC class I-dependent manner to antigen-specific CD8 T cells [ 3 , 28 ]. In vitro studies suggested that inflamed BMECs triggered full activation of naïve CD8 T cells leading to their proliferation and differentiation to cytotoxic effector CD8 T cells [ 3 ].…”

“…However, two independent studies showed that BMECs can take up exogenous antigen from their abluminal side in vitro and in vivo , process and cross-present it on their luminal side in an MHC class I-dependent manner to antigen-specific CD8 T cells [ 3 , 28 ]. In vitro studies suggested that inflamed BMECs triggered full activation of naïve CD8 T cells leading to their proliferation and differentiation to cytotoxic effector CD8 T cells [ 3 ]. Thus, either BMECs possess the entire machinery required for cross-presentation of antigen on MHC class I molecules or MHC class I-peptide complexes on BMECs may suffice to activate naïve CD8 T cells as previously shown for naïve CD8 T-cell activation in APC-free systems [ 41 , 89 ].…”

“…This would require firm interaction of the T-cell receptor with peptide-MHC class I complexes on BMECs under physiological flow. Investigating CD8 T-cell interaction with BMECs in the absence and presence of their cognate antigen and/or functional expression of MHC class I by in vitro live cell imaging showed no involvement of endothelial antigen presentation in mediating the initial arrest of CD8 T cells on BMECs under physiological flow [ 3 , 42 ]. Rather, MHC class I-restricted antigen presentation influenced post-arrest behaviour of CD8 T cells on BMECs by abrogating their crawling and subsequent diapedesis, leading to CD8 T-cell-mediated apoptosis of BMECs [ 3 , 42 ].…”

Regulation of autoimmune‐mediated neuroinflammation by endothelial cells

“…Accordingly, primary mouse brain microvascular ECs (pMBMECs) stimulated in vitro with TNF-α and IFN-γ capture exogenous Ags from their abluminal side that they process and present via MHCI molecules on their luminal side to naïve CD8 + T cells. This promotes CD8 + T-cell differentiation into cytotoxic T cells (CTLs) that induce BEC apoptosis and subsequent dismantling of the pMBMEC monolayer [62]. Interestingly, Ag presentation by ECs inhibits naïve and effector CD8 + T cells crawling and diapedesis through the pMBMEC monolayer to rather favor their stationary and probing behavior [62].…”

IQGAP2 regulates blood-brain barrier immune dynamics

“…BECs facilitate this process through the expression of various receptors, such as leukocyte adhesion molecules (LAMs), that allow interactions with and extravasation of leukocytes into tissue beds ( 15 , 16 ). In addition, BEC chemokine signaling and antigen presentation ( 17–19 ) also play a key role in orchestrating leukocyte extravasation. While the underlying molecular mechanisms of leukocyte extravasation are similar across all organs, BECs have been shown to express very low levels of LAMs under homeostatic conditions, making them refractory to mild inflammatory cues ( 1 , 20 ).…”