TY - JOUR
T1 - Platelet EVs contain an active proteasome involved in protein processing for antigen presentation via MHC-I molecules
AU - Marcoux, Genevieve
AU - Laroche, Audrée
AU - Hasse, Stephan
AU - Bellio, Marie
AU - Mbarik, Maroua
AU - Tamagne, Marie
AU - Allaeys, Isabelle
AU - Zufferey, Anne
AU - Lévesque, Tania
AU - Rebetz, Johan
AU - Karakeussian-Rimbaud, Annie
AU - Turgeon, Julie
AU - Bourgoin, Sylvain G
AU - Hamzeh-Cognasse, Hind
AU - Cognasse, Fabrice
AU - Kapur, Rick
AU - Semple, John W
AU - Hébert, Marie-Josée
AU - Pirenne, France
AU - Overkleeft, Herman S
AU - Florea, Bogdan I
AU - Dieude, Mélanie
AU - Vingert, Benoît
AU - Boilard, Eric
N1 - © 2021 by The American Society of Hematology.
PY - 2021/12/23
Y1 - 2021/12/23
N2 - In addition to their hemostatic role, platelets play a significant role in immunity. Once activated, platelets release extracellular vesicles (EVs) formed by the budding of their cytoplasmic membranes. Because of their heterogeneity, platelet EVs (PEVs) are thought to perform diverse functions. It is unknown, however, whether the proteasome is transferred from platelets to PEVs or whether its function is retained. We hypothesized that functional protein processing and antigen presentation machinery are transferred to PEVs by activated platelets. Using molecular and functional assays, we found that the active 20S proteasome was enriched in PEVs, along with major histocompatibility complex class I (MHC-I) and lymphocyte costimulatory molecules (CD40L and OX40L). Proteasome-containing PEVs were identified in healthy donor blood, but did not increase in platelet concentrates that caused adverse transfusion reactions. They were augmented, however, after immune complex injections in mice. The complete biodistribution of murine PEVs after injection into mice revealed that they principally reached lymphoid organs, such as spleen and lymph nodes, in addition to the bone marrow, and to a lesser extent, liver and lungs. The PEV proteasome processed exogenous ovalbumin (OVA) and loaded its antigenic peptide onto MHC-I molecules, which promoted OVA-specific CD8+ T-lymphocyte proliferation. These results suggest that PEVs contribute to adaptive immunity through cross-presentation of antigens and have privileged access to immune cells through the lymphatic system, a tissue location that is inaccessible to platelets.
AB - In addition to their hemostatic role, platelets play a significant role in immunity. Once activated, platelets release extracellular vesicles (EVs) formed by the budding of their cytoplasmic membranes. Because of their heterogeneity, platelet EVs (PEVs) are thought to perform diverse functions. It is unknown, however, whether the proteasome is transferred from platelets to PEVs or whether its function is retained. We hypothesized that functional protein processing and antigen presentation machinery are transferred to PEVs by activated platelets. Using molecular and functional assays, we found that the active 20S proteasome was enriched in PEVs, along with major histocompatibility complex class I (MHC-I) and lymphocyte costimulatory molecules (CD40L and OX40L). Proteasome-containing PEVs were identified in healthy donor blood, but did not increase in platelet concentrates that caused adverse transfusion reactions. They were augmented, however, after immune complex injections in mice. The complete biodistribution of murine PEVs after injection into mice revealed that they principally reached lymphoid organs, such as spleen and lymph nodes, in addition to the bone marrow, and to a lesser extent, liver and lungs. The PEV proteasome processed exogenous ovalbumin (OVA) and loaded its antigenic peptide onto MHC-I molecules, which promoted OVA-specific CD8+ T-lymphocyte proliferation. These results suggest that PEVs contribute to adaptive immunity through cross-presentation of antigens and have privileged access to immune cells through the lymphatic system, a tissue location that is inaccessible to platelets.
KW - Animals
KW - Antigen Presentation
KW - Blood Platelets/chemistry
KW - Extracellular Vesicles/chemistry
KW - Histocompatibility Antigens Class I/analysis
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Proteasome Endopeptidase Complex/analysis
U2 - 10.1182/blood.2020009957
DO - 10.1182/blood.2020009957
M3 - Article
C2 - 34293122
SN - 1528-0020
VL - 138
SP - 2607
EP - 2620
JO - Blood
JF - Blood
IS - 25
ER -