Perivascular macrophages create an intravascular niche for CD8⁺ T cell localisation prior to the onset of fatal experimental cerebral malaria

Abstract

Objectives The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)‐infected mice show only minor clinical signs. Methods A 2‐photon intravital microscopy (2P‐IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM. Results Early in the disease course, antigen‐specific CD8 + T cells came in contact and arrested on the endothelium of post‐capillary venules. CD8 + T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post‐capillary venules. Closer examination revealed that CD8 + T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post‐capillary venules. ‘Activity hotspots’ in large post‐capillary venules were characterised by T‐cell localisation, activated morphology and clustering of PVM, increased abutting of post‐capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8 + T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short‐term interactions with the inner vessel wall at hotspots. Conclusion Our study suggests an active interaction between PVM and CD8 + T cells occurs across the blood–brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology.

T cell activation niches—Optimizing T cell effector function in inflamed and infected tissues*

“…Initial tissue entry may be random, with the niche being assembled de novo at sites where incoming effector T cells happen to encounter cognate APCs in the perivascular space. The spatial relationship between these initial activation hubs and the infection foci itself is also not known, but it is likely that the initial activation event upon entry into the tissue will necessitate a subsequent relocation of that expanded effector T cell pool to the infection site for pathogen clearance, as previously predicted 119,122 …”

“…A growing body of evidence points to the de novo assembly of microanatomical activation hubs located perivascularly that are induced following immune challenge and that underpin T cell immunity within inflamed tissues. 4,5,7,8,86,[117][118][119]…”

“…A similar phenomenon was observed in a model of fetal cerebral malaria in which T cells were initially associated with perivascular APCs but were found to be moving rapidly throughout the tissue in later stages of the disease. 119 This points to a two-step process in peripheral tissues wherein antigen-specific T cells become reactivated at perivascular niches during the early response and then, as functionally poised effectors, remain in the tissue to deliver effector cytokines that contribute to pathogen control or immunopathology.…”

“…While the recent study of the adventitial cuff suggests this pre‐positioned innate activation niche can also serve as a site for subsequent effector T cell activation, 103 it remains unclear whether the induced clustering of effector T cells with APCs seen in many inflamed tissues (Table 1) arises at predetermined locations within the tissue parenchyma. A growing body of evidence points to the de novo assembly of microanatomical activation hubs located perivascularly that are induced following immune challenge and that underpin T cell immunity within inflamed tissues 4,5,7,8,86,117‐119 …”

Perivascular macrophages in theCNS: From health to neurovascular diseases

“…In normal condition, they are necessary for the maintenance of BBB, but in the case of CNS injury and neuroinflammation, they seem to mediate the damage of BBB. Most recently, PVMs have been confirmed to participate in BBB disruption through the release of cytotoxic mediators under malaria 90 . What's more, another review analyzed literature from 2000 to 2021 and revealed that PVMs could cause BBB damage in Alzheimer's disease (AD) 91 …”