Apoptosis leads to the fragmentation and packaging of cellular contents into discrete vesicles, a process known as 'blebbing'. Extracellular vesicles express membrane-bound sialic acids, which enable their capture by CD169 (sialoadhesin; Siglec-1) expressing macrophages in the lymph node and spleen. Furthermore, CD169 mediates vesicle trafficking and suppresses the immune response to exosomes-a type of extracellular vesicle released from living cells. In this study, we found that CD169(+) macrophages were the predominant splenic macrophage subset responsible for the capture of EL4 lymphoma-derived apoptotic vesicles (ApoVs) from circulation. CD169(-/-) mice had significantly enhanced in vivo cytotoxic T lymphocyte responses to antigen-pulsed ApoVs, indicating a suppressive role for CD169(+) macrophages to ApoV-associated antigen. In contrast to the observed immunogenic role of ApoVs, the co-administration of unpulsed ApoVs with antigen-pulsed dendritic cells (DCs) significantly suppressed DC-mediated cytotoxic response in vivo; however, this occurred independent of CD169 expression. Overall, our results confirm that apoptosis contributes to both tolerance and immunity, as well as establishing CD169 as a critical mediator of the immune response to extracellular vesicles.