Abstract
Dendritic cells (DCs) are professional antigen-presenting cells playing a central role in connecting innate and adaptive immunity. Maturation signals are, however, required for DCs to undergo phenotypic and functional changes to acquire a fully competent antigen-presenting capacity. We previously reported that activated apoptotic peripheral lymphocytes (ActApo) provide activation/maturation signals to human monocyte-derived DCs. In this paper, we have characterized the signaling pathways and molecules involved in ActApo-mediated DC maturation. We found that both cellular and supernatant fractions from ActApo are required for DC maturation signaling. ActApoSup-induced CD80 and CD86 expression was significantly blocked in the presence of neutralizing antibodies against tumor necrosis factor-α (TNF-α). Cell-cell contact-dependent signaling involved β2 integrins, dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), and TLR4 because ActApo-induced up-regulation of the maturation markers CD80 and CD86 was significantly inhibited in the presence of neutralizing antibodies against CD18, CD11a, CD11b, and DC-SIGN as well as TLR4. The role of TLR4 was further confirmed by silencing of TLR4 in DCs. In addition, the endogenous adjuvant effect exerted by activated apoptotic splenocytes (ActApoSp) was reduced after immunization with human serum albumin in TLR4(-/-) mice. We detected activation of multiple signaling pathways and transcription factors in DCs upon co-culture with ActApo, including p38, JNK, PI3K-Akt, Src family kinases, NFκB p65, and AP1 transcription factor family members c-Jun and c-Fos, demonstrating the complex interactions occurring between ActApo and DCs. These studies provide important mechanistic insight into the responses of DCs during encounter with cells undergoing immunogenic cell death.
Highlights
Activated apoptotic lymphocytes provide activation/maturation signals to human monocyte-derived dendritic cells (DCs)
We revealed that TNF-␣ present in the supernatant fractions from activated apoptotic peripheral lymphocytes (ActApo) can in part induce DC maturation and that cell-cell contact-dependent signaling involving 2 integrins, dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), and TLR4 was needed
We observed partial up-regulation of maturation markers on DCs (Fig. 1A). These results suggested that both cell-cell contact and soluble factors are required for ActApo-induced DC maturation
Summary
Activated apoptotic lymphocytes provide activation/maturation signals to human monocyte-derived dendritic cells (DCs). We characterized the intracellular signaling pathways involved in ActApo-induced DC maturation Both PI3K-Akt and Src family tyrosine kinases are involved in activation of p38 MAPK, which in turn regulates activation of transcription factors NFB and c-Fos, whereas PI3K-Akt-independent but Src family kinase-dependent JNK MAPK activation regulates activation of transcription factor c-Jun. Both PI3K-Akt and Src family tyrosine kinases are involved in activation of p38 MAPK, which in turn regulates activation of transcription factors NFB and c-Fos, whereas PI3K-Akt-independent but Src family kinase-dependent JNK MAPK activation regulates activation of transcription factor c-Jun These results provide an important insight into the molecules and signaling pathways engaged in DC-ActApo interaction, which can be used to further improve the immunogenicity of vaccine vectors under development
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