title: Hypoxia-induced and A2A adenosine receptor-independent T-cell suppression is short lived and easily reversible.
abstract: Tissue hypoxia plays a key role in establishing an immunosuppressive environment in vivo by, among other effects, increasing the level of extracellular adenosine, which then signals through A2A adenosine receptor (A2AR) to elicit its immunosuppressive effect. Although the important role of the adenosine--A2AR interaction in limiting inflammation has been established, the current study revisited this issue by asking whether hypoxia can also exert its T-cell inhibitory effects even without A2AR. A similar degree of hypoxia-triggered inhibition was observed in wild-type and A2AR-deficient T cells both in vitro and, after exposure of mice to a hypoxic atmosphere, in vivo. This A2AR-independent hypoxic T-cell suppression was qualitatively and mechanistically different from immunosuppression by A2AR stimulation. The A2AR-independent hypoxic immunosuppression strongly reduced T-cell proliferation, while IFN-γ-producing activity was more susceptible to the A2AR-dependent inhibition. In contrast to the sustained functional impairment after A2AR-mediated T-cell inhibition, the A2AR-independent inhibition under hypoxia was short lived, as evidenced by the quick recovery of IFN-γ-producing activity upon re-stimulation. These data support the view that T-cell inhibition by hypoxia can be mediated by multiple mechanisms and that both A2AR and key molecules in the A2AR-independent T-cell inhibition should be targeted to overcome the hypoxia-related immunosuppression in infected tissues and tumors.
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115, USA.
authors.forename: Akio
authors.initials: A
authors.lastname: Ohta
authors.forename: Manasa
authors.initials: M
authors.lastname: Madasu
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Subramanian
authors.forename: Radhika
authors.initials: R
authors.lastname: Kini
authors.forename: Graham
authors.initials: G
authors.lastname: Jones
authors.forename: Alexander
authors.initials: A
authors.lastname: Choukèr
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohta
authors.forename: Michail
authors.initials: M
authors.lastname: Sitkovsky
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D000860:Hypoxia / Q000276:immunology*; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D043705:Receptor, Adenosine A2A; D007371:Interferon-gamma; D000241:Adenosine
keywords: IFN-γ; immunosuppression; inflammation; oxygen; tumor microenvironment