MOLECULAR AND CELLULAR MECHANISMS IN ASTROCYTE-T CELL CROSS-TALK

Migration of encephalitogenic T cells into the brain parenchima through the blood–brain barrier (BBB) is a crucial feature for initiating tissue injury in different neuroinflammatory diseases. The BBB is comprised of astrocyte processes and endothelial cells, which form the lumen of the brain microvasculature and help in maintaining immune quiescence through contact-dependent mechanisms as well as release of soluble factors. Activated CD4+ T cells may establish physical contacts with astrocytes, thereby reciprocally influencing cellular activity and functions. In addition, astrocytes and CD4 T cells may communicate through the secretion of soluble signaling molecules during contact. Among molecules secreted by astrocyte, ATP is a key messenger which can also signal to CD4 T cell through purinergic P2 receptors. Our results show that activated CD4+ T cells inhibit calcium oscillations in astrocytes through direct modulation of extracellular ATP levels. This effect correlated with the expression of plasma membrane ectonucleoside triphosphate diphosphohydrolase CD39, which is induced by contact of the activated T cell with astrocyte. In addition, T cell contact with astrocyte results in the upregulation of the ecto-5’-nucleotidase CD73, which converts AMP to adenosine. This effect was peculiar of T cell contact with astrocyte since it did not occur with microglia or peritoneal macrophages. Pharmacological inhibition of Ca2+ oscillations in astrocyte completely prevented CD73 induction on T cell, thus suggesting that a gliostrasmitter released by astrocyte in a Ca2+-dependent fashion might be responsible of this effect. Since degradation of ATP to adenosine by CD73 regulates BBB permeability and leukocytes infiltration into the brain this regulatory circuit might have important pathogenetic implications in multiple sclerosis and other neuroinflammatory conditions. Finally, functional characterization of T cell upon contact with astrocyte allowed us to assess a proinflammatory phenotype and Th17 skewing albeit with important differences, such as CD39 and CD73 expression, with respect to conventionally activated cells. Thus, we characterized an astrocyte specific signature of T cell activation, which might be important in the pathogenesis of neuroinflammatory disorders.