November 2015 | Volume 212, No. 12
Brief Definitive Reports
- Identification of a novel cis-regulatory element essential for immune tolerance
LaFlam et al. identify a novel and highly conserved noncoding DNA element, ACNS1, essential for Aire expression and immune tolerance regulation in thymic epithelial cells. They show that ACNS1 is an NF-κB–responsive element and that its loss results in development of spontaneous autoimmunity in mice.
- Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease
Mutations in the catalytic subunit of the γ-secretase complex, Presenilin, cause familial Alzheimer’s disease. Analysis of patients’ brains shows that these mutations do not result in loss of enzymatic function but in qualitative changes in Aβ product profiles.
- Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection
The transcription factor Zeb2 cooperates with T-bet to control NK cell maturation, viability, and exit from the bone marrow and is essential for rejection of melanoma lung metastasis.
- Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection
In response to viral infections, activated CD8+ T cells differentiate into terminal effector and memory T cells. This developmental process is controlled by the transcriptional repressor Zeb2, which acts downstream of T-bet.
- The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection
Dominguez et al. show that high amounts of T-bet induce the transcription factor Zeb2 in LMCV-specific CTLs. These transcription factors act in concert to restrict the memory program and drive terminal effector gene expression.
- Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
Ladang et al. report that Elp3, a subunit of the Elongator complex, is induced by Wnt signaling and is required to initiate colon cancer development through the regulation of Sox9 translation. They also show that this mechanism is relevant in radiation-induced intestinal regeneration.
- TLR9 ligation in pancreatic stellate cells promotes tumorigenesis
Zambirinis et al. show that TLR9 stimulation has a protumorigenic effect in pancreatic carcinoma by inducing pancreatic stellate cells to become fibrogenic and produce chemokines that stimulate epithelial cell proliferation. Activation of TLR9 results also in an immune suppressive tumor microenvironment via recruitment of regulatory T cells and induction of myeloid-derived suppressor cell proliferation.
- Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance
Palmer et al. find that Cish, a member of the SOCS family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumor. The authors uncover a novel mechanism of suppression for a SOCS member.
- Oct1 and OCA-B are selectively required for CD4 memory T cell function
Shakya et al. identify the transcription factor Oct1 and its cofactor OCA-B as central mediators for generating memory T cell responses in mice.
- CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow
Nakamura-Ishizu et al. report that megakaryocytes function as a niche to maintain HSC quiescence through CLEC-2–mediated production of Thpo and other key regulators of HSC function. These findings could enable manipulation of HSCs for clinical application.
- Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis
Briot et al. show that inflammatory lipids deriving from a high-fat diet suppress NOTCH1 expression and signaling in adult arterial endothelium and propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of atherosclerosis.
- DNAM-1 controls NK cell activation via an ITT-like motif
DNAM-1–mediated active biochemical signals initiated by a conserved ITT-like motif are essential for its capacity to enhance NK cell cytotoxicity and cytokine production. Enhancement of these signals may underlie the therapeutic impact of blocking anti-TIGIT antibodies for treatment of cancer and viral infections.