Abstract: Astrocytes play important roles in the central nervous system (CNS) to support and regulate CNS function. They are abundant type of glia that form a meshwork of interconnected cells almost completely tiling the CNS. Each astrocyte extends densely ramified processes that establish close contacts and interaction with other astrocytes, neurons and blood vessels, placing these cells in an ideal position to control extracellular milieu and to exert global effects on CNS physiology. Astrocytes are dynamic cells that continuously sense and respond to the physiological and pathological cues within their local environment. This responsiveness of astrocytes and their intercellular communication with neighboring cells in the CNS principally relies on increase in intracellular Ca2+ and release of neuroactive compounds such as adenosine 5′-triphosphate (ATP), that are critical for maintaining proper CNS function (Butt, 2011; Bazargani and Attwell, 2016). Intracellular Ca2+ level in astrocytes is under the control of diverse ionotropic and metabotropic receptors that upon activation promote Ca2+ entry into the cell or its liberation from cellular Ca2+ stores. This promotes rise of Ca2+ signals in astrocytes that spread information between astrocytes themselves and toward neurons to regulate CNS function. When CNS environment becomes disturbed following injury or in disease, astrocytes generally respond with an augmentation of Ca2+ signaling within their network that has deleterious effects and drive pathological processes (Shigetomi et al., 2019). Thus, Ca2+ signaling acts as a powerful and highly adaptable system for astrocyte communication with neighboring cells in the CNS and enables astrocytes to detect and respond to changes in their local environment in both, physiological and pathological conditions. In our recent paper (Bijelić et al., 2020) we show that astrocyte Ca2+ signals controlled by purinergic P2X7 ionotropic receptors are also important for astrocytic communication with specific immune cells that infiltrate into the CNS in experimental autoimmune encephalomyelitis, a commonly used animal model of multiple sclerosis. We show that astrocytes respond to the nearby autoreactive CD4+ T cells with an increase in their intracellular Ca2+ (Figure 1), hinting at the previously unrecognized involvement of astrocytic Ca2+ signaling in the nervous system-immune system communication in an autoimmune disease of CNS.