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The National Institute of Allergy and Infectious Diseases (NIAID) hosted a two-day virtual workshop on leveraging microbial exposure to improve mouse models of human immune status and disease. The workshop’s objective was to evaluate the current state of knowledge in the field and to identify gaps, challenges and future directions.

How aging, immunity and cancer are related is incompletely understood. Data now show altered differentiation and loss of function of tumor-infiltrating T cells with aging. So-called T_TAD cells seem to be involved.

Cancer and aging are associated with each other, but underlying mechanisms contributing to this correlation are unclear. Here the authors identify a dysfunctional T cell state that is distinct from typical T cell exhaustion and only occurs in the tumor microenvironment during later life.

Our work identifies previously unrecognized functional heterogeneity in tissue-resident interstitial macrophages. We have identified ten macrophage subsets, each thought to specifically contribute to recruiting and organizing cell types within tissues. Moreover, our findings suggest the diversity and division of labor extend to other macrophage populations previously considered homogeneous.

In this Resource paper, the authors integrate T cell antigen receptor, B cell antigen receptor and exome sequencing comparing early and metastatic breast cancer in humans, showing how the immune response and tumors coevolve.

Jakubzick and colleagues show that interstitial macrophages across various tissues display similar coordinated chemokine signatures in humans and mice.

Singh and colleagues show Tigit controls the generation of germinal center-derived plasma cell precursors that give rise to long-lived differentiated progeny in the bone marrow.

In this Review, the authors analyze evidence for autoimmunity against components of antimicrobial immunity, metaphorically represented by the mythical ouroboros snake eating its own tail.

Homeostatic immune cells remain perpetually vigilant against pathogens. We found that baseline JAK–STAT signaling supports the characteristic transcriptional and epigenetic state of homeostatic T cells and macrophages in mice. JAK–STAT signaling under homeostatic conditions was driven by signals from healthy tissue and did not require external immune stimuli.

We report two patients with biallelic SHARPIN deficiency, which manifests with autoinflammation and B cell immunodeficiency and is phenotypically distinct from Sharpin deficiency in mice. In one patient, there was a significant shift from pro-survival signaling to cell-death signaling in fibroblasts and lymphoblasts induced by members of the TNF cytokine superfamily, accounting for the autoinflammation and immunodeficiency. Targeted therapy with TNF inhibitors had a dramatic beneficial effect.

Here the authors show that sepsis and its resolution alter cancer susceptibility by epigenetically altering resident macrophages resulting in retention of T cells that increase antitumoral immunity.

The transient expression of CD61 and its unconventional pairing with CD103 at the immune synapse enhances T cell receptor signaling, improves anti-tumor cytotoxicity and mitigates tumor growth. Clinically, CD61⁺ tumor infiltrating lymphocytes (TILs) exhibit enhanced effector functions and show limited cellular exhaustion.

In this study, the authors suggest that in the lung ApoE is a checkpoint for monocyte-to-macrophage differentiation triggered by the dectin1–Card9 pathway.

The microbiome is known to affect antitumor immune responses, but how this occurs is unclear. Rhamnose-rich polysaccharides (RHP) from a commensal strain of Lactiplantibacillus plantarum have now been shown to induce iron sequestration by tumor macrophages, thereby limiting tumor growth and promoting antitumor immunity.

Here the authors show that a heteropolysaccharide from a commensal bacteria commonly found in the Korean food kimchi is able to bolster antitumor immune responses by instructing tumor-associated macrophages to release lipocalin-2, which sequesters iron away from tumor cells contributing to the immune response to attack these cells.

Bock and colleagues perform integrative analysis of JAK-STAT mutant mice and find JAK-STAT signaling regulates CD8⁺ T cell and macrophage homeostasis by contributing to a poised epigenetic and transcription-regulatory state, preparing cells to rapidly respond to stimuli.