TNIK signaling imprints CD8+ T cell memory formation early after priming

Abstract

Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8 + T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8 + T cells induces a TNIK-dependent nuclear translocation of β-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8 + T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells.

State-dependent protein-protein interactions mediating 4-1BB CAR Signaling

“…QMI measures Proteins in Shared ComplexES (PiSCES), so to maximize protein complex detection, so we added several of the most connected nodes in Fig 1E to our previously-described QMI panel, which was built to measure the amount of co-association among critical TCR signalosome members 14,21 : CAR (anti-2A scar, IP only), TRAF1, TRAF2 and BIRC3. We also included three proteins that did not reach statistical significance in the mass spec experiments, but are known to be important to the TRAF and NFκB signalosome in lymphocytes: TAK1 (MAP3K7, FC=597, t=−1.09 NS), which is recruited by TAB1/2 and signals to IKKb 18 and was recently shown to be critical to IFNγ production in CD8+ T cells in a large CRISPR screen 33 ; TNIK (found in only 1 co-IP experiment) which binds TRAFs, may recruit NCK to link TRAFs with TCR signaling mechanisms 13 , and is critical for CD8+ T cell memory formation 34 ; and SHARPIN (FC=13.6, T=−1.21), a component of the linear ubiquitination complex (LUBAC) that promotes activation of the IKK complex downstream of TNF family receptors 35,36 , ubiquitinates CARMA-BCL10-MALT complex 37 , and may bind directly to TRAF1 38 . As previously described 21,32,39 , we identified two antibodies that could simultaneously bind each target in its native state on flow cytometry beads, and validated target specificity using cell lysates lacking the target (Fig S2 and Table S2).…”

The Microenvironment That Regulates Vascular Wall Stem/Progenitor Cells in Vascular Injury and Repair

“…Lymphoid Tissue. Lymphoid tissue is also known as immune tissue, which plays a major role in the mucosal local anti-infective immunity [22]. In addition, lymphoid tissue and lymphocytes have some effect on the physiological and pathological activities of VW-S/PCs.…”

Stem cell-like memory T cells: The generation and application

“…In addition to the direct activation by Wnt protein, Wnt signaling pathway can also be activated by TNF receptor super family (TNFRSF) such as CD27 and 4‐1BB. As a downstream molecule of TNFRSF, TRAF2‐/NCK‐interacting kinase (TNIK) has shown to activate Wnt pathway by inducing the nuclear localization of β‐catenin 11 …”

“…As one of the downstream molecules of CD27, TNIK promotes the activation of the Wnt pathway. TNIK‐deficient T cells have shown preferential differentiation into short‐lived effector cells 11 . In acute myeloid leukemia, blocking CD27‐CD70 signal strongly decreased stem cell signature and inhibited proliferation of malignant cells, leading to decreased cancer cell load and increased survival time 68 …”