Dataset Information

TRAILshort disrupts T cell receptor signaling and promotes immune tolerance in vivo

ABSTRACT: TRAIL is a TNF family ligand that trimerizes upon engaging TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NFκB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. Here, we show that elevated TRAILshort levels are associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrate that TRAILshort binding to DR5 recruits and activates the phosphatase SHP-1, leading to ZAP-70 dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promotes persistence of transformed MEFs and L428 Hodgkin lymphoma and antagonizes CD19 CAR T cell activity, revealing TRAILshort as an immunosuppressive modulator of T cell function with potential therapeutic implications in TRAILshort-high diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, T Cell

SUBMITTER: Dong-Gi Mun

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD078420 | Pride | 2026-05-20

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	CD4_Tcell.xlsx	Xlsx
	Eclispe_2022May10_DGM_Tcell_Phospho_FN01.raw	Raw
	Eclispe_2022May10_DGM_Tcell_Phospho_FN02.raw	Raw
	Eclispe_2022May10_DGM_Tcell_Phospho_FN03.raw	Raw
	Eclispe_2022May10_DGM_Tcell_Phospho_FN04.raw	Raw

Items per page:

1 - 5 of 42

Similar Datasets

Project description:TRAIL cytotoxicity is exploited as anti-cancer therapy since many years, however incomplete knowledge is generating many obstacles. Here, we address whether the highly abundant extracellular matrix molecule tenascin-C (TNC) orchestrating an immune suppressive tumor microenvironment and binding TRAIL impacts TRAIL cytotoxicity. We used an immune competent autologous NT193 breast cancer model with a knockdown (KD) of Tnfsf10 (encoding TRAIL) and observed accelerated tumor growth marked by less apoptosis, more proliferation and less myeloid cell infiltration as seen by flow cytometry. Grafting the same Tnfsf10 KD cells into a TNC knockout host showed repressed tumor growth suggesting that TNC is involved in regulating TRAIL functions. In vitro, we saw reduced macrophage invasion and phagocytosis with conditioned medium from Tnfsf10 KD tumor cells proposing a role of TRAIL in counteracting tumor growth. We further demonstrated that TRAIL increases secretion of TGF2/3 inducing CXCR4 in macrophages. Here, we have discovered regulation of TRAIL cytotoxicity through cell plasticity orchestrated by TNC. The pro-tumorigenic effects of TNC, counteracting TRAIL cytotoxicity, entail repression of Tnfsf10 through integrin and, abolishing TRAIL-receptor DR5 and E-cadherin expression. As the MAREMO peptide MP5 inhibits TNC actions, we determined whether targeting TNC with MP5 has an impact on TRAIL cytotoxicity. Indeed, MP5 enforces an epithelial phenotype and elevates DR5 expression thus causing sensitization to TRAIL-induced cell death. Moreover, MP5 inhibited tumor growth that was less pronounced in Tnfsf10 KD tumors suggesting MP5 to empower endogenous TRAIL cytotoxicity. Kaplan-Meier analysis demonstrated that a high TRAIL expression correlates with favorable breast and gastric cancer patient survival which is abolished when TNC levels are also high. Our results predict that tumors with lower TNC might be more responsive to therapeutic TRAIL cytotoxicity and that MP5 could be a novel tool for enhancing TRAIL therapy.

Dataset Information

TRAILshort disrupts T cell receptor signaling and promotes immune tolerance in vivo

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets