Issues

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.

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.

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.

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.

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.

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.

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.

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.

Shakya et al. identify the transcription factor Oct1 and its cofactor OCA-B as central mediators for generating memory T cell responses in mice.

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.

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–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.