TY - JOUR
T1 - CD73 expression on extracellular vesicles derived from CD4(+) CD25(+) Foxp3(+) T cells contributes to their regulatory function
AU - Smyth, Lesley Ann
AU - Ratnasothy, Kulachelvy
AU - Tsang, Julia Y S
AU - Boardman, Dominic
AU - Warley, Alice
AU - Lechler, Robert
AU - Lombardi, Giovanna
PY - 2013/9
Y1 - 2013/9
N2 - CD4(+) CD25(+) Foxp3(+) T regulatory (Treg) cells maintain immunological tolerance. In this study the possibility that Treg cells control immune responses via the production of secreted membrane vesicles, such as exosomes, was investigated. Exosomes are released by many cell types, including T cells, and have regulatory functions. Indeed, TCR activation of both freshly isolated Treg cells and an antigen-specific Treg-cell line resulted in the production of exosomes as defined morphologically by electron microscopy (EM) and by the presence of tetraspanin molecules LAMP-1/CD63 and CD81. Expression of the ecto-5-nucleotide enzyme CD73 by Treg cells has been shown to contribute to their suppressive function by converting extracellular AMP to adenosine, which, following interaction with adenosine receptors expressed on target cells, leads to immune modulation. CD73 was evident on Treg-cell-derived exosomes, accordingly when these exosomes were incubated in the presence of AMP production of adenosine was observed. Most importantly, CD73 present on Treg-cell-derived exosomes was essential for their suppressive function hitherto exosomes derived from a CD73-negative CD4(+) T-cell line did not have such capabilities. Overall our findings demonstrate that CD73-expressing exosomes produced by Treg cells following activation contribute to their suppressive activity through the production of adenosine.
AB - CD4(+) CD25(+) Foxp3(+) T regulatory (Treg) cells maintain immunological tolerance. In this study the possibility that Treg cells control immune responses via the production of secreted membrane vesicles, such as exosomes, was investigated. Exosomes are released by many cell types, including T cells, and have regulatory functions. Indeed, TCR activation of both freshly isolated Treg cells and an antigen-specific Treg-cell line resulted in the production of exosomes as defined morphologically by electron microscopy (EM) and by the presence of tetraspanin molecules LAMP-1/CD63 and CD81. Expression of the ecto-5-nucleotide enzyme CD73 by Treg cells has been shown to contribute to their suppressive function by converting extracellular AMP to adenosine, which, following interaction with adenosine receptors expressed on target cells, leads to immune modulation. CD73 was evident on Treg-cell-derived exosomes, accordingly when these exosomes were incubated in the presence of AMP production of adenosine was observed. Most importantly, CD73 present on Treg-cell-derived exosomes was essential for their suppressive function hitherto exosomes derived from a CD73-negative CD4(+) T-cell line did not have such capabilities. Overall our findings demonstrate that CD73-expressing exosomes produced by Treg cells following activation contribute to their suppressive activity through the production of adenosine.
U2 - 10.1002/eji.201242909
DO - 10.1002/eji.201242909
M3 - Article
C2 - 23749427
SN - 0014-2980
VL - 43
SP - 2430
EP - 2440
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 9
M1 - N/A
ER -