Microglia and Perivascular Macrophages Act as Antigen Presenting Cells to Promote CD8 T Cell Infiltration of the Brain

Goddery, Emma; Fain, Cori E.; Lipovsky, Chloe G; Ayasoufi, Katayoun; Yokanovich, Lila T.; Malo, Courtney S.; Khadka, Roman H.; Tritz, Zachariah P.; Jin, Fang; Hansen, Michael J.; Johnson, Aaron J.

doi:10.3389/fimmu.2021.726421

Cited by 73 publications

(38 citation statements)

References 67 publications

(87 reference statements)

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“…These genes included Axl , Bhlhe40 , Cd274 , Ctsb , Ctss , Spp1 and others, which were previously identified as widely regulated by microglia in many different conditions [ 53 , 57 , 129 ]. The upregulation of these genes allow microglia to react to perturbation, enabling them to phagocytose damaged cells and other material ( Axl , C1qa , C1qb ) [ 130 – 134 ], interact and communicate with recruited lymphocytes ( B2m , Cd274 , H2-D1 ) [ 135 , 136 ], process and metabolize myelin debris and other detritus ( Ch25h , Lpl ) [ 137 , 138 ], produce secondary inflammatory mediators ( Ccl3 , Ctsb , Ctsc , Ctss, Trim25 ) [ 139 – 144 ] and other functions. Furthermore, Bhlhe40 was identified as a danger response gene and is suggested to be a putative transcription factor which regulates microglial cell activity in response to disturbances in their local environment [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes

West

McCorkindale

Guennewig

et al. 2022

J Neuroinflammation

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Background Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. Methods Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders. Results We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer’s disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia. Conclusions Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes

West

McCorkindale

Guennewig

et al. 2022

J Neuroinflammation

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“…Microglia perform multiple roles within the CNS. While they are best known for their capacity to migrate through the CNS to facilitate the detection of foreign material and cellular debris, they are also capable of antigen presentation, phagocytosing myelin, and providing support for neural stem cell proliferation [15][16][17][18]. Microglia are guided towards injured or dead cells via their capacity to sense and respond to chemical gradients of molecules such as adenosine triphosphate (ATP) or lipopolysaccharide (LPS).…”

Section: General Biological Functions Of Microgliamentioning

confidence: 99%

Single-Cell RNA-Sequencing: Astrocyte and Microglial Heterogeneity in Health and Disease

Spurgat

Tang

2022

Cells

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Astrocytes and microglia are non-neuronal cells that maintain homeostasis within the central nervous system via their capacity to regulate neuronal transmission and prune synapses. Both astrocytes and microglia can undergo morphological and transcriptomic changes in response to infection with human immunodeficiency virus (HIV). While both astrocytes and microglia can be infected with HIV, HIV viral proteins in the local environment can interact with and activate these cells. Given that both astrocytes and microglia play critical roles in maintaining neuronal function, it will be critical to have an understanding of their heterogeneity and to identify genes and mechanisms that modulate their responses to HIV. Heterogeneity may include a depletion or increase in one or more astrocyte or microglial subtypes in different regions of the brain or spine as well as the gain or loss of a specific function. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool that can be used to characterise these changes within a given population. The use of this method facilitates the identification of subtypes and changes in cellular transcriptomes that develop in response to activation and various disease processes. In this review, we will examine recent studies that have used scRNA-seq to explore astrocyte and microglial heterogeneity in neurodegenerative diseases including Alzheimer’s disease and amyotrophic lateral sclerosis as well as in response to HIV infection. A careful review of these studies will expand our current understanding of cellular heterogeneity at homeostasis and in response to specific disease states.

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“…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]…”

Section: Induced Activation Nichesmentioning

confidence: 99%

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

Bala

McGurk

Zilch

et al. 2021

Immunological Reviews

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Successful immunity to infection, malignancy, and tissue damage requires the coordinated recruitment of numerous immune cell subsets to target tissues. Once within the target tissue, effector T cells rely on local chemotactic cues and structural cues from the tissue matrix to navigate the tissue, interact with antigen‐presenting cells, and release effector cytokines. This highly dynamic process has been “caught on camera” in situ by intravital multiphoton imaging. Initial studies revealed a surprising randomness to the pattern of T cell migration through inflamed tissues, behavior thought to facilitate chance encounters with rare antigen‐bearing cells. Subsequent tissue‐wide visualization has uncovered a high degree of spatial preference when it comes to T cell activation. Here, we discuss the basic tenants of a successful effector T cell activation niche, taking cues from the dynamics of Tfh positioning in the lymph node germinal center. In peripheral tissues, steady‐state microanatomical organization may direct the location of “pop‐up” de novo activation niches, often observed as perivascular clusters, that support early effector T cell activation. These perivascular activation niches appear to be regulated by site‐specific chemokines that coordinate the recruitment of dendritic cells and other innate cells for local T cell activation, survival, and optimized effector function.

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Microglia and Perivascular Macrophages Act as Antigen Presenting Cells to Promote CD8 T Cell Infiltration of the Brain

Cited by 73 publications

References 67 publications

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes

Single-Cell RNA-Sequencing: Astrocyte and Microglial Heterogeneity in Health and Disease

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

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