Beta2-adrenergic receptor signaling in CD4(+) Foxp3(+) regulatory T cells enhances their suppressive function in a PKA-dependent manner

Author(s)

Guereschi, Marcia G. ^[1] ; Araujo, Leandro P. ^[1] ; Maricato, Juliana T. ^[1] ; Takenaka, Maisa C. ^[1] ; Nascimento, Vanessa M. ^[1] ; Vivanco, Bruno C. ^[1] ; Reis, Vanessa O. ^[1] ; Keller, Alexandre C. ^[1] ; Brum, Patricia C. ^[2] ; Basso, Alexandre S. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04023062 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo - Brazil

• Document type: Journal article
• Source: European Journal of Immunology; v. 43, n. 4, p. 1001-1012, APR 2013.
• Web of Science Citations: 53

Abstract

Beta2-adrenergic receptor (B2AR) signaling is known to impair Th1-cell differentiation and function in a cAMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-. CD4+ Foxp3+ Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3+ Treg cells express functional B2AR. B2AR activation in Treg cells leads to increased intracellular cAMP levels and to protein kinase A (PKA)-dependent CREB phosphorylation. We also found that signaling via B2AR enhances the in vitro suppressive activity of Treg cells. B2AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 mRNA levels in responder CD4+ T cells and improved Treg-cell-induced conversion of CD4+ Foxp3 cells into Foxp3+ induced Treg cells. Moreover, B2AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2AR signaling. (AU)

• FAPESP's process: 09/51886-3 - Neuroimmunomodulation: drugs, stress and cytokines on nervous, endocrine and immune systems relationships
• Grantee: João Palermo Neto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 08/58564-9 - Study of adaptive immune response modulation by the sympathetic nervous system: emphasis on autoimmunity, Th17 cells and Foxp3 + regulatory T cells
• Grantee: Alexandre Salgado Basso
• Support Opportunities: Research Grants - Young Investigators Grants