RIP2 Contributes to Expanded CD4+ T Cell IFN-γ Production during Efferocytosis of Streptococcus pneumoniae–Infected Apoptotic Cells

Abstract

Apoptotic cell clearance by professional and nonprofessional phagocytes in the process of efferocytosis is critical to preserve tissue homeostasis. Uptake of apoptotic cells by dendritic cells generates regulatory T cells and induces immunologic tolerance against self-antigens. In contrast, ingestion of infected apoptotic cells promotes activation of TLR4/MyD88-dependent bone marrow-derived dendritic cells (BMDCs) and triggers Th17 cell differentiation. In this study, we evaluated the impact of Streptococcus pneumoniae-infected apoptotic cell efferocytosis by BMDCs derived from C57BL/6 mice on differentiation and expansion of CD4 + T cell subsets, as well as the role of TLR2/4 and receptor-interacting protein 2 (RIP2) receptors in recognizing intracellular pathogens during efferocytosis. We demonstrated that BMDC-mediated efferocytosis of S. pneumoniae-infected apoptotic cells induced Th1 cell differentiation and expansion. Although TLR2/4 and RIP2 deficiency in BMDCs did not affect Th1 cell differentiation during efferocytosis, the absence of RIP2 decreased IFN-g production by CD4 T cells during the expansion phase. These findings suggest that RIP2-mediated IL-1b production during efferocytosis of S. pneumoniae-infected apoptotic cells partially supports a Th1-mediated IFN-g production microenvironment.

Unveiling efferocytosis-related signatures through the integration of single-cell analysis and machine learning: a predictive framework for prognosis and immunotherapy response in hepatocellular carcinoma

“…Neutrophils, an indispensable entity within the immune system, exert cytotoxic effects on infected and cancerous cells, while also participating in efferocytosis for the clearance of deceased cells ( 17 ). Furthermore, dendritic cells and other immune cells actively contribute to the intricate process of efferocytosis ( 18 , 19 ). Intriguingly, specific malignant tumor cells express receptors and ligands associated with efferocytosis, facilitating their engulfment of apoptotic cells within their microenvironment and aiding in immune evasion ( 20 , 21 ).…”

Efferocytosis signatures as prognostic markers for revealing immune landscape and predicting immunotherapy response in hepatocellular carcinoma

“…“Efferocytosis” refers to the process by which one cell engulfs another cell, usually referring to macrophages engulfing apoptotic cells ( Zhou et al, 2020a ; Wang et al, 2023b ). In addition, there are other cells such as neutrophils, which release DNA fiber networks during the inflammatory process and can engulf these DNA fiber networks and cell debris on DNA ( Bukong et al, 2018 ; Lee et al, 2022 ); natural killer cells (NK cells), which are usually part of the immune system and can kill infected cells or cancer cells, and can also clear dead cells through efferocytosis ( Jensen et al, 2020 ); malignant tumor cells, some of which can express efferocytosis-related receptors and ligands, enabling them to engulf surrounding apoptotic cells and evade the immune system’s attack ( Brightwell et al, 2016 ; Zhang et al, 2022 ); dendritic cells and some other immune cells also play a role in efferocytosis ( Maschalidi et al, 2022 ; Nino-Castano et al, 2022 ). The function of efferocytosis in tumors is complex and can sometimes promote tumor development and other times inhibit it ( Banerjee et al, 2021 ; Tajbakhsh et al, 2021 ; Lin et al, 2022 ).…”