Volume 24 Issue 5, May 2023

Orthogonal engineering of adoptively transferred CD8⁺ T cells to co-express two cytokines — an IL-2Rβ/γ-biased IL-2 variant and the proinflammatory alarmin IL-33 — induces an exhaustion-resistant synthetic cell state with potent anti-tumor efficacy in the absence of host pre-conditioning.

APLAID is a very rare autoinflammatory disease thought to be caused by mutations in PLCG2. A mouse model of APLAID recapitulates clinical features of the disease, and identifies a crucial function for G-CSF that might be targeted therapeutically.

The immune system is not immune to sex differences. New research now uncovers the molecular mechanisms that underlie sex-based differences during antiviral immune responses.

New work from Udeochu, Amin, Huang, and colleagues provides mechanistic insights into how the tau protein engages the cGAS–STING pathway to elicit antiviral responses in Alzheimer’s disease. This signaling axis diminishes the MEF2C transcriptional network in neurons critical for maintaining cognitive function.

Mononuclear phagocyte proliferation is thought to be limited to myeloid progenitor cells and mature macrophages. However, availability within an interstitial macrophage niche permits the proliferation of monocytes in the lung before macrophage differentiation.

A blood single-cell atlas of human sepsis identifies subsets of immune-suppressive neutrophils in people at high risk.

When an interstitial macrophage niche is empty, classical monocytes can proliferate locally in a manner that is restricted by the transcription factor MAFB, before undergoing differentiation into distinct macrophage subsets. These findings reveal a new function of monocytes and highlight the complex regulation of proliferation and differentiation during macrophage development.

Regulatory T (T_reg) cells respond to interferon-γ (IFNγ) during viral infection and polarize to a T helper (T_H)1-like state. Such T_reg cells possess effector functions, such as the production of IFNγ, yet remain stable and potently limit virus-specific effector T cell function, CD8⁺ T cell proliferation and the formation of central memory T cells.

We show a crucial protective function for T follicular helper (T_FH)-like cells localized within granuloma-associated lymphoid tissue for Mycobacterium tuberculosis control in mouse models of tuberculosis. Antigen-specific B cells contribute to this strategic localization and the maturation of cytokine-producing T_FH-like cells.

We engineered CD8⁺ T cells with two orthogonal cytokines for adoptive cell transfer into mice with solid tumors. These cells acquired a novel synthetic effector state that fully deviated from TOX⁺ canonical exhaustion and displayed improved anti-tumor effector functions.

The adipose tissue is rich in immune cells. In this Review, the authors cover adipose tissue myeloid cells and how they control and respond to inflammation and pathology.

Knight and colleagues report altered granulopoiesis and increased frequency of immature neutrophil subsets with immunosuppressive properties in a subset of patients with sepsis with poor outcome.

Cheng et al. demonstrate that an extra copy of the X-linked epigenetic regulator UTX in females increases natural killer (NK) cell effector function. As NK cells are critical for antiviral immunity, this may explain decreased severity of viral infections in females compared to males.

In non-small cell lung cancer, the presence of monocyte-derived macrophages inversely correlates with the presence of NK cells. Merad and colleagues propose that when monocytes phagocytose tumor debris they express TREM2, become pro-tumorigenic, and suppress NK cell recruitment and activation in tumors.

NK cells require an immunological synapse to kill cancer cells and these synapses have been shown to have membranous protrusions. Here the authors use cutting-edge imaging and other techniques to show that tumor serine metabolism results in a reduction in NK cell sphingomyelin content and a lack of these membranous protrusions, which could contribute to a failure to kill cancer cells.

APLAID is a rare autoinflammatory disorder driven by mutations in PLCG2. Here the authors provide a new mouse model using the human APLAID p.Ser707Tyr mutation. The mouse recapitulates clinical features of APLAID that can be prevented by anti-G-CSF. Individuals with APLAID were also shown to have high circulating levels of G-CSF suggesting this might be a suitable target for the clinic.

Marichal and colleagues use a model of niche depletion and refilling to show that engrafted Ly6C⁺ classical monocytes proliferate locally in a Csf1 receptor-dependent manner before differentiating into lung interstitial macrophages.

Here the authors show that unlike IL12, IFNγ can induce a T helper 1-like state in regulatory T (T_reg) cells during viral infection in mice that suppresses effector T cell responses and memory formation.

Khader and colleagues show Mycobacterium tuberculosis (Mtb)-specific B cells are needed to recruit T_FH cells into follicular-like structures within lung granulomas to control the Mtb bacilli; however, specific antibodies and many conventional properties of B cells are dispensable.

Coukos, Corria-Osorio and colleagues use an orthogonal genetic approach to engineer CD8⁺ T cells into better effector synthetic cells for antitumor adoptive cell therapy. This approach generates engineered effector T cells that express an IL-2 variant, IL-33 and a programmed cell death protein 1 decoy.