Ectonucleotidase activity and immunosuppression in astrocyte-CD4 T cell bidirectional signaling

Abstract

Astrocytes play a crucial role in neuroinflammation as part of the glia limitans, which regulates infiltration of the brain parenchyma by leukocytes. The signaling pathways and molecular events, which result from the interaction of activated T cells with astrocytes are poorly defined. Here we show that astrocytes promote the expression and enzymatic activity of CD39 and CD73 ectonucleotidases in recently activated CD4 cells by a contact dependent mechanism that is independent of T cell receptor interaction with class II major histocompatibility complex (MHC). Transforming growth factor-β (TGF-β) is robustly upregulated and sufficient to promote ectonucleotidases expression. T cell adhesion to astrocyte results in differentiation to an immunosuppressive phenotype defined by expression of the transcription factor Rorγt, which characterizes the CD4 T helper 17 subset. CD39 activity in T cells in turn inhibits spontaneous calcium oscillations in astrocytes that correlated with enhanced and reduced transcription of CCL2 chemokine and Sonic hedgehog (Shh), respectively. We hypothesize this TCR-independent interaction promote an immunosuppressive program in T cells to control possible brain injury by deregulated T cell activation during neuroinflammation. On the other hand, the increased secretion of CCL2 with concomitant reduction of Shh might promote leukocytes extravasation into the brain parenchyma.

A T Cell Suppressive Circuitry Mediated by CD39 and Regulated by ShcC/Rai Is Induced in Astrocytes by Encephalitogenic T Cells

“…Astrocytes have been demonstrated to suppress recently activated CD4 + T cells by inducing the upregulation of CD39/CD73 on their surface, which correlates with the acquisition of an immunosuppressive Th17 phenotype (8). Whether inflammatory T cells can in turn affect the expression of these ATP-degrading enzymes in astrocytes, and the role of Rai in this process, have as yet not been explored.…”

“…Astrocytes contribute to neuroinflammation in multiple sclerosis and in the mouse experimental autoimmune encephalomyelitis (EAE) model by promoting encephalitogenic T-cell activation through their ability to act as antigen presenting cells (APC) and to upregulate the T-cell costimulatory molecules B7-1 and B7-2 (3–6). Intriguingly, T-cell suppression by astrocytes has also been documented, resulting from their ability to promote antigen-independent surface upregulation of inhibitory molecules on T cells, including the inhibitory receptor CTLA-4 and the ectonucleotidases CD39 and CD73 (7, 8). Additionally, astrocytes actively influence the generation and maintenance of effector T cells both by modulating CD4 + T-cell polarization to Th1 cells and by supporting IL-2-dependent Treg cell survival (9, 10).…”

“…Astrocytes are themselves targets of infiltrating autoreactive T cells. Antigen-independent, contact-dependent upregulation of the integrin ligands VCAM-1 and ICAM-1 on astrocytes cocultured with activated T cells has been reported (8). Additionally, infiltrating Th1 and Th17 cells modulate astrocyte function via contact-independent mechanisms involving the release of inflammatory mediators that promote astrocytic secretion of pro-inflammatory cytokines and chemokines while repressing expression of anti-inflammatory cytokines (12–15).…”

Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia

“…Astrocytes are pivotal elements in the regulation of BBB permeability, and they express ICAM-1 (CD54) and VCAM-1 (CD105), which are ligands for LFA-1 (aLb2) and VLA-4 (a4b1) integrins, respectively. These integrins, which are expressed at the cell surface in T-ALL cells [13], mediate the adherence of activated CD4 cells to astrocytes as well as the bidirectional signaling that affects CD4 cell function and BBB permeability [31]. It could be hypothesized that integrin-mediated interaction of T-ALL cells with astrocytes at the BBB might limit their potential to infiltrate the neuroparenchyma.…”

Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1‐integrin

“…To obtain pure neuronal cultures, cytoarabinoside-C (4 lM) has been added at DIV3. Mouse astrocytes were prepared from P2 WT pups, and pure cultures of astrocytes (> 99.5%) were obtained by shaking flasks for 24 h at 37°C at days 2 and 6 after plating (Filipello et al, 2016). The cells were maintained in EMEM (Life Technologies, Carlsbad, CA, USA), 20% glucose, 1% Pen/Strep (Lonza, Basel, Switzerland) with 10% FBS (EuroClone, Milan, Italy).…”