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Monocytes play an important part in the clearance of pathogens during infection. Yasmine Belkaid and her colleagues now report that inflammatory monocytes can also have a regulatory role. Specifically, these cells can mitigate the tissue damage induced by neutrophils during infection of mice with Toxoplasma gondii by releasing prostaglandin E2 in response to commensal bacteria.

Defined skin commensal bacteria elicit a dermal dendritic-cell-dependent, long-lasting, commensal-specific CD8⁺ T-cell response that promotes protection against pathogens while preserving tissue homeostasis.

In a post hoc multiomics analysis of a trial comparing a plant-based, low-fat diet to an animal-based, ketogenic diet, the diets have differential effects on peripheral immune cell frequencies and immune-related gene expression.

IgA-secreting plasma cells that originate in the intestine are found in the meninges, where they protect the brain against pathogens.

A study reveals that the skin acts as an autonomous lymphoid organ, producing antibodies to control the local biomass of the microbiota and protect against systemic infection, maintaining homeostasis between the host and its microbiota.

Staphylococcus epidermidis induces a potent, durable and specific antibody response that is conserved in humans and non-human primates, and which could be redirected against pathogens as a new form of topical vaccination.

Patients who express a hyperactive mutant of the kinase PI3K exhibit defective humoral immunity. Preite et al. show that overactive PI3K leads to defective class-switched antigen-specific responses to immunization, despite augmented germinal-center formation and reactivity to commensal microbes and self antigens.

Regulatory T cells come in many different forms depending on their mode of action or developmental origin. Data now show that interleukin 35, an immunomodulatory cytokine secreted by regulatory T cells, and interleukin 10 induce so-called 'iT_R35 cells', which may have an important role in the phenomenon of infectious tolerance.

Genetic background affects how macrophages integrate multiple stimuli, e.g., to IL-4 in tissue environments. BALB/c macrophages show different transcriptional and epigenomic remodeling compared to C57BL/6, leading to distinct synergistic LPS responses.

Bhandoola and colleagues describe the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice, and which may be conserved in humans.

To survive a given infection, a host needs to mount a controlled immune response. Regulatory T cells are important components of the regulatory network, which benefit the host by limiting immunopathology but may also be detrimental to the host by favouring pathogen survival.

Lazarevic and colleagues show that the transcription factor EGR2 controls a transcriptional program specific to pathogenic T_H17 cells in the CNS.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.

Yang and colleagues report that MAIT cells are present in the meninges where they play an essential role in repressing tissue ROS accumulation and preserving meningeal barrier integrity.

Kubo et al. report two kindreds that exhibit a deficiency of iRHOM2, which interacts with ADAM17, leading to defective release of TNF and CD62L and resulting in altered immune responses to opportunistic infections.

CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth.

Nie et al. show that the transcription factor LRF, by upregulating expression of the integrin gene Itgb7, imprints thymic precursors of CD8αα⁺ intraepithelial lymphocytes for eventual seeding of the gut tissues.

The authors use a machine-learning approach to uncover confounding variables in studies that seek to establish an association between the gut microbiota and human disease.

The skin is home to diverse microbial communities that constantly interact with host epithelial and immune cells. In this Review, the authors summarize how the skin microbiota can control innate and adaptive immunity to skin pathogens, as well as its influence on skin inflammatory diseases.

The transition of the fetus from the womb to the external world represents an extraordinary challenge. The generation of memory T cells before birth may serve an important role in preparation for this fundamental transition.

Tim-3, a member of the T cell immunoglobulin mucin family, is expressed by T_H1 cells. Analysis of Tim-3–Tim3 ligand signaling now shows this pathway is intimately involved in the counter-regulation of T helper type 1 immune responses.

Commensal microbes are necessary for proper development of the immune system. Here Zanvit et al. show that neonatal antibiotics treatment causes long-term changes in the gut and skin microbiomes, and exacerbates immune-mediated skin pathology at adult age in mouse experimental models of psoriasis.

Cytokines that signal via IL-20R have been linked to autoinflammatory skin disease, but their role in infection is poorly understood. Datta and colleagues show that IL-20R signaling suppresses the production of IL-1β and IL-17 and dampens skin antibacterial responses.

The transcription factor ThPOK promotes CD4⁺ T cell differentiation in the thymus. Bosselut and colleagues show that ThPOK maintains CD4⁺ T lineage integrity and is required for proper T_H1 and T_H2 differentiation.

Group 3 innate lymphoid cells have low expression of the transcription factor GATA-3. Zhu and colleagues show that despite its low expression, GATA-3 is essential for the homeostasis, further maturation and effector function of lineage-committed group 3 innate lymphoid cells.

Antibiotic treatment of SIV-infected nonhuman primates shows that inducing bacterial dysbiosis in the gut—similar to that seen in HIV infection—does not promote disease progression, questioning its potential role in progression to HIV/AIDS.

The transcription factor c-MAF is required for the generation of Helicobacter-specific regulatory T cells that selectively restrain pro-inflammatory T_H17 cells; the absence of c-MAF in mouse regulatory T cells results in pathobiont-dependent inflammatory bowel disease.

Conditional knockout of the protease furin in CD4⁺ T cells is shown to result in impaired peripheral tolerance and autoimmune disease. Furin deficiency compromises TGF-β release and T_reg function, and is associated with inherently more aggressive effector T cells.

Distinct populations of lymphocytes act sequentially during development to direct maturation of the mammalian gut microbiota.

The alarmin interleukin-33 is constitutively expressed at barrier sites and released in response to tissue damage; here, the IL-33 receptor ST2 is shown to be preferentially expressed on colonic regulatory T cells, where it promotes regulatory T-cell function and adaptation to the inflammatory tissue environment.

CD4⁺ T cells that selectively produce interleukin (IL)-17 (T_H17 cells) are essential for host defence and autoimmunity. It has been thought that IL-6 and transforming growth factor (TGF)-β1 are the factors responsible for initiating the specification of T_H17 cells. Here, however, it is shown that T_H17 differentiation can occur in the absence of TGF-β signalling. IL-6, IL-23 and IL-1β effectively induced IL-17 production in naive precursors. These data reveal an alternative mode for T_H17 differentiation and the importance of IL-23.

Our skin is home to millions of bacteria, fungi and viruses that comprise the skin microbiota. In this Review, Byrd and colleagues discuss recent insights into skin microbial communities, including their composition in health and disease, dynamics between species and interactions with the immune system.