B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Abstract

Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the bloodbrain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4 + T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immuneregulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.neuroinflammation | multiple sclerosis | spontaneous EAE | CNS lesion distribution | blood-brain barrier M ultiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Disease pathogenesis is initiated by peripheral activation of autoimmune T lymphocytes by yet unknown mechanisms, followed by T-cell expansion and subsequent migration across the complex structure of the blood-brain barrier (BBB). Within the CNS, entry of this first wave of T cells elicits recruitment of other immune cells, which together evoke a local inflammatory process ultimately resulting in demyelination, as well as axonal and neuronal damage (1). Several histological MS subtypes have been described with regard to lesion distribution and cellular composition (2). The reasons underlying distinct lesion development at different anatomical sites still remain however largely elusive: Some authors have proposed that the nature and expression pattern of the target autoantigen might play a role (3, 4). Others have observed an influence of the HLA complex and its role in shaping antigen presentation, thus suggesting that T-cell antigen specificity might impact the location of inflammation (5). Additionally, T-cell polarization into distinct T helper subtypes, as well as their expression pattern of chemokine receptors and adhesion molecules, has been implicated in determining the lo...

Upregulation of Bcl-2 and Its Promoter Signals in CD4+ T Cells during Neuromyelitis Optica Remission

“…This indicates that AQP4-IgG–specific CD4+ T cells participates in the genesis of NMO and that T cells appear to be equally crucial for the full development of the immunopathogenetic cascade (Vaknin-Dembinsky et al, 2012). Previous studies have identified the myelin/MOG specific T cells to be CD4+ cells in spontaneous CNS autoimmunity and NMO like diseases (Dasgupta and Dasgupta, 2016; Klotz et al, 2016; Tostanoski et al, 2016). Once the T cell is stimulated by agents such as TNF-α and IL-1β, the phosphorylated MAP3K7 could phosphorylate IκB, which has the ability to phosphorylate NFκB (DiDonato et al, 1997).…”

Blood–brain barrier and its function during inflammation and autoimmunity

“…137 Interestingly, lack of PD-L1 in transgenic mice that harbors MOGspecific TCR as well as MOG-specific immunoglobulin-heavy chain B cells show increased BBB permeability, and T cell infiltration in the cerebrum, brain stem and cerebellum with higher EAE incidence and severity. 137 The inhibition of protein kinase C-beta, an important signal transduction molecule that regulates several physiologic and inflammatory responses has shown to improve the BBB function and control CNS damage during EAE. 138 It has been found that BBB endothelium up-regulates the expression of adenosine A2A receptor during neuroinflammation, and treatment with its antagonist SCH-58261 reduced the BBB permeability, improve TJ architecture, and control the reactive astrocytes and microglia, suggesting that inflammationassociated extracellular adenosine induces inflammatory changes in the BBB ECs.…”

“…The interaction of myelin‐specific effector CD4 + T cells with the brain ECs is crucial in regulating the BBB integrity, and strategies to control these interactions are considered as promising approach to control BBB leakiness and inflammatory cell migration into the CNS. A recent study shows that deletion of a negative costimulatory molecule, B7‐H1 (PD‐L1) in MOG‐specific CD4 + T cells lead to increased effector function, and these cells showed IFN‐γ and granzyme‐B‐mediated increase in the BBB permeability in a contact‐dependent manner . Interestingly, lack of PD‐L1 in transgenic mice that harbors MOG‐specific TCR as well as MOG‐specific immunoglobulin‐heavy chain B cells show increased BBB permeability, and T cell infiltration in the cerebrum, brain stem and cerebellum with higher EAE incidence and severity .…”

“…A recent study shows that deletion of a negative costimulatory molecule, B7‐H1 (PD‐L1) in MOG‐specific CD4 + T cells lead to increased effector function, and these cells showed IFN‐γ and granzyme‐B‐mediated increase in the BBB permeability in a contact‐dependent manner . Interestingly, lack of PD‐L1 in transgenic mice that harbors MOG‐specific TCR as well as MOG‐specific immunoglobulin‐heavy chain B cells show increased BBB permeability, and T cell infiltration in the cerebrum, brain stem and cerebellum with higher EAE incidence and severity . The inhibition of protein kinase C‐beta, an important signal transduction molecule that regulates several physiologic and inflammatory responses has shown to improve the BBB function and control CNS damage during EAE .…”

Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma

“…The surprising observation that genetic loss of CTLA‐4 during adulthood conferred a complete resistance to EAE demonstrate the opposing roles of this molecule at different stages of development. The role of PD‐1 was also explored in EAE were the interaction between PD‐1 and PD‐L1 but not PD‐L2 axis in regulating CNS autoimmunity is critical. LAG‐3 deficiency, instead, can also lead to autoimmunity, but only in predisposed genetic backgrounds, such as non‐obese diabetic (NOD) mice, where spontaneous emergence of diabetes was accelerated .…”