Characterization of regulatory T cells in psoriatic arthritis patients: role of type I interferons in restraining cAMP-mediated immune suppression, and implications for metabolic inflammation.

Proponente Fabrizio Conti - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca

Psoriatic Arthritis (PsA) is a chronic inflammatory arthropathy commonly associated with psoriasis (PsO). Several evidences suggest a critical role of the immune cells, especially T cells, in the pathogenesis of PsA. Regulatory T cells (Tregs), a subset of FOXP3+ CD4 T cells endowed with multiple immunosuppressive functions, play key roles in preventing unwanted immune responses. Reduced frequencies of circulating Tregs was revealed in a variety of autoimmune disorders including PsA. Tregs suppress target cells by transferring cyclic adenosine monophosphate (cAMP), an intracellular second messenger, through gap junctions; notably, cAMP intracellular levels are especially high in Tregs compared to conventional T cells (Tconvs) mostly because of a constitutively low expression of phosphodiesterases (PDEs). Treg suppression results in impaired calcium influx in target cells, and defects in this process was reported in autoimmunity. An increased expression of type-I interferon (IFN)-induced gene signature has been reported in PsA. Type I IFN inhibits human Treg suppressive function by repressing their intracellular cAMP levels in a PDE4-dependent fashion.
The aims of this project are to assess whether Tregs show lower frequency, altered phenotype, and less cAMP content, while Tconvs display defective suppression of calcium influx, ex vivo from PsA patients compared to healthy controls; to evaluate whether the expression of IFN-stimulated genes is increased in PsA patient and correlates to the extent of Treg functional defects, to disease activity and severity and to test whether, in vitro, treatment with PDE inhibitors can rescue normal cAMP levels and suppressive functions in Tregs from PsA patients.

LS4_8, LS6_2, LS6_3

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