T cell physiology

 

The immune system protects the body against foreign pathogens while respecting self tissue components. Pivotal regulators of immune system homeostasis are T cells, which bear on their surface clonotypic receptors (TCRs). Adenosine triphosphate (ATP) is the source of chemical energy for most cellular functions and is also released in the extracellular space by eukaryotic cells where it acts as signaling molecule by activating purinergic P2 receptors. We study the purinergic regulation of T cell physiology. Purinergic receptors are divided into non-selective cation channels (P2X subtype) and G protein-coupled receptors (P2Y subtype). In T cells P2X7 is the most abundant subtype; its stimulation has a profound effect on the response and metabolism of the T cell. Inhibition of P2X7 causes T cell anergy and promotes the polarization of naive CD4 cells towards the immunosuppressive T regulatory phenotype. In contrast, prolonged stimulation or high concentrations of ATP determines the opening of a pore permeable to molecules of molecular weight up to 900 Da and cell death . We are characterizing the role of P2X7 in the homeostasis of T cells and adaptive immunity in different physiological and pathological conditions. In particular, we are studying the role of P2X7 in the metabolism of T cell, in the regulation of gut-associated lymphoid system and the modulation of mucosal immunity.

 

- The T cell in blood-brain barrier regulation 

The migration of T cells into the brain parenchyma through the blood-brain barrier (BBB) formed by astrocytes and endothelial cells is a crucial pathogenetic aspect in several neuroinflammatory diseases. Among the molecules secreted by astrocytes, ATP constitutes a fundamental signal. Contact with astrocytes induces the expression of the plasma membrane ectonucleoside triphosphate diphosphohydrolase CD39 and ecto-5'-nucleotidase CD73 in the T cell. The combined action of these two enzymes generates adenosine, which promotes the permeability of the BBB. We study this regulatory circuit that could have important implications in the pathogenesis of multiple sclerosis and other neuroinflammatory conditions.

 

- Mucosal immunity in the pathogenesis of Omenn syndrome

Mice with Rag2^R229Q/R229Q hypomorphic mutation represents a faithful model of Omenn syndrome (OS), a rare primary immunodeficiency with autoimmune manifestations. In OS and more generally in patients with immunodeficiency, protracted cycles of antibiotics affect mucosal commensalism and can generate dysbiosis with consequent intestinal immunopathological alterations. The characterization of the microbiome and local adaptive immune response in these animals will allow hypothesizing new therapeutic protocols for patients with OS.

 

Contacts

Prof. Fabio Grassi

 

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Department Biometra, via G.B. Viotti 3/5, 20133 Milan, Italy