Issues

In this important study, Jain et al. find that chronic TREM2 activation by AL002a antibody exacerbates the seeding and spread of pathological tau, enhances the disease-associated microglial signature, and increases neurite dystrophy in 5xFAD mice seeded with Alzheimer’s disease tau.

In this issue of JEM, Jenster et al. investigate how UVB radiation promotes activation of the inflammatory immune sensor NLRP1, and in doing so uncover how NLRP1 recognizes a diverse range of ribotoxic stresses.

ITLN1, whose expression is regulated by the unfolded protein response, coats a subset of microorganisms, including Akkermansia muciniphila, allows them to thin the inner mucus layer, and increases colitis severity. ITLN1 upregulation in UC may drive similar outcomes.

The results of this study show that chronic administration of a mouse TREM2 agonist antibody in a model of Aβ amyloidosis increases microglial activation, seeded neuritic plaque tau pathology, and neuritic dystrophy without affecting Aβ plaque burden or conformation.

Jenster et al. describe how p38 signaling integrates cues of cellular stress to activate human NLRP1 by direct phosphorylation. This novel pathway is activated by physiologically relevant threats to the skin, including the UVB-triggered ribotoxic stress response or infection with alphaviruses, such as Chikungunya virus.

ITLN1, whose expression is regulated by the unfolded protein response, coats a subset of microorganisms, including Akkermansia muciniphila, allows them to thin the inner mucus layer, and increases colitis severity. ITLN1 upregulation in UC may drive similar outcomes.

Using scRNA-seq and scTCR-seq, Kasmani, Zander, and colleagues identify multiple branching pathways regulating CD8 T cell differentiation during chronic viral infection. An intermediate subset is shown to arise from progenitor cells and bifurcate into both terminal effector and exhausted subsets.

Inherited ITK deficiency shows incomplete penetrance for severe EBV disease and can underlie severe tuberculosis due to insufficient IFN-γ production by innate-like adaptive (Vδ2⁺ γδ T and MAIT) and purely adaptive αβ T lymphocytes.

Intact B cell responses to SARS-CoV-2 mRNA vaccines in patients with genetic or acquired type I IFN deficiencies suggest that type I IFNs induced by mRNA vaccines are not required for vaccine efficacy.

Integrins mediate the localization of innate-like B cells to the marginal zone of the spleen. By analyzing mice with β1-integrin deficiency in mature B cells, Andreani et al. show that β1-integrin is also required for normal differentiation and function of marginal zone B cells.

Platelets from NSCLC patients express and release high amounts of TLT-1, a platelet-specific TREM family member, that promotes tumor growth by suppressing CD8 T cells. Antibody-mediated blockade of platelet TLT-1 reduces tumor progression in mouse and rescues NSCLC patients’ CD8 T cells ex vivo.

Inactivation of TCF7, a WNT transcriptional mediator, in CD4⁺ T cells or pharmacological inhibition of ligand-mediated WNT signaling results in increased CD8⁺ T cell infiltration and reduced pancreatic cancer growth, identifying WNT signaling as a regulator of the pancreatic cancer immune microenvironment.

Loss of the dNTPase and DNA repair enzyme SAMHD1 is associated with cancer and causes systemic autoimmunity. We show transformation-promoting spontaneous DNA damage and MDA5-driven, but cGAS/STING-dependent, chronic type I interferon production in SAMHD1-deficient mice.

The study identifies proteolytic processing of ANGPTL4 as a molecular switch mechanism converting a protumorigenic molecule into a systemically acting antitumorigenic molecule and discovers nANGPTL4 as a novel antimetastatic therapeutic agent.

The authors identify a tumor-suppressing angiocrine function of CCL2 which is inhibited by tumor-derived adrenomedullin acting via its receptor on endothelial cells. Disinhibition of endothelial CCL2 results in reduced tumor progression through inhibition of adrenomedullin formation by tumor cells.