TCAIM Decreases T Cell Priming Capacity of Dendritic Cells by Inhibiting TLR-Induced Ca2+ Influx and IL-2 Production

Abstract

We previously showed that the T cell activation inhibitor, mitochondrial (Tcaim) is highly expressed in grafts of tolerance-developing transplant recipients and that the encoded protein is localized within mitochondria. In this study, we show that CD11c+ dendritic cells (DCs), as main producers of TCAIM, downregulate Tcaim expression after LPS stimulation or in vivo alloantigen challenge. LPS-stimulated TCAIM-overexpressing bone marrow–derived DC (BMDCs) have a reduced capacity to induce proliferation of and cytokine expression by cocultured allogeneic T cells; this is not due to diminished upregulation of MHC or costimulatory molecules. Transcriptional profiling also revealed normal LPS-mediated upregulation of the majority of genes involved in TLR signaling. However, TCAIM BMDCs did not induce Il2 mRNA expression upon LPS stimulation in comparison with Control-BMDCs. In addition, TCAIM overexpression abolished LPS-mediated Ca2+ influx and mitochondrial reactive oxygen species formation. Addition of IL-2 to BMDC–T cell cocultures restored the priming capacity of TCAIM BMDCs for cocultured allogeneic CD8+ T cells. Furthermore, BMDCs of IL-2–deficient mice showed similarly abolished LPS-induced T cell priming as TCAIM-overexpressing wild type BMDCs. Thus, TCAIM interferes with TLR4 signaling in BMDCs and subsequently impairs their T cell priming capacity, which supports its role for tolerance induction.

Connexin 43 in splenic lymphocytes is involved in the regulation of CD4+CD25+ T lymphocyte proliferation and cytokine production in hypertensive inflammation

“…These results clearly demonstrate that Cx mimetic peptide Gap27 inhibits the ConA-induced lymphocyte activation and proliferative response in vitro . The proliferation and activation of T lymphocytes and the synthesis and secretion of pro-inflammatory cytokines are regulated by intracellular Ca 2+ levels ( 51 ). The increase in intracellular Ca 2+ is a key step in the cascade of signals that results in T cell proliferation ( 52 ).…”

Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance

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Inhibition of Extracellular Calcium Influx Results in Enhanced IL-12 Production in LPS-Treated Murine Macrophages by Downregulation of the CaMKKβ-AMPK-SIRT1 Signaling Pathway

“…Extracellular calcium influx across the plasma membrane is a major source for the increase of intracellular calcium, which acts as a crucial secondary messenger in regulating macrophage activation, such as phagosomes maturation, activation of NLRP3 inflammasome, and transcriptional control of cytokines [ 7 – 9 ]. Microbial components (LPS, etc.)…”