Interleukin-17 (IL-17)-producing γδ T (Tγδ17) cells are innate-like mediators of intestinal barrier immunity. Although IL-17-producing helper T cell and group 3 innate lymphoid cell plasticity have been extensively studied, the mechanisms governing Tγδ17 cell effector flexibility remain undefined. Here, we combined type 3 fate mapping with single-cell ATAC-sequencing/RNA-sequencing multiome profiling to define the cellular features and regulatory networks underlying Tγδ17 cell plasticity. During homeostasis, Tγδ17 cell effector identity was stable across tissues, including for intestinal T-bet+ Tγδ17 cells that restrained interferon-γ production. However, Salmonella enterica subsp. enterica serovar Typhimurium infection induced intestinal Vγ6+ Tγδ17 cell conversion into type 1 effectors, with loss of IL-17A production and partial RORγt downregulation. Multiome analysis revealed a trajectory along Vγ6+ Tγδ17 cell effector conversion, with TIM-3 marking ex-Tγδ17 cells with enhanced type 1 functionality. Last, we characterized and validated a critical AP-1 regulatory axis centered around JUNB and FOSL2 that controls Vγ6+ Tγδ17 cell plasticity by stabilizing type 3 identity and restricting type 1 effector conversion. Ciofani and colleagues examine the plasticity of Tγδ17 cells in the gut, where they identify a role for the AP-1 transcription factors JUNB and FOSL2 in restricting type 1 plasticity.

Understanding the initiation of T-helper (Th)-2 immunity is crucial for addressing allergic diseases that have been linked to the commensal microbiota. However, Th2 responses are notably absent from known host-microbiota intestinal immune circuits. Notably, the commensal protist Tritrichomonas induces a transient innate ILC2 circuit rather than a chronic Th2 circuit. Canonical Th2 responses rely on the induction of IL-4 production by innate cells. This study shows that the absence of Tet2 , a DNA demethylase, reprograms naïve T cells to autonomously produce IL-4 upon T cell receptor stimulation, bypassing the need for IL-4 from innate cells for Th2 differentiation. Loss of this checkpoint induces chronic Th2 responses to Tritrichomonas , associated with IL-25-dependent barrier dysfunction and increased susceptibility to allergic pathology in response to dietary antigens. Sentence Summary:Regulation of cell autonomous IL-4 in T cells is critical to prevent dysregulated Th2 immunity to commensals and predisposition to allergy.

γδ T cells are the first T cell lineage to develop in the thymus and take up residence in a wide variety of tissues where they can provide fast, innate-like sources of effector cytokines for barrier defense. In contrast to conventional αβ T cells that egress the thymus as naïve cells, γδ T cells can be programmed for effector function during development in the thymus. Understanding the molecular mechanisms that determine γδ T cell effector fate is of great interest due to the wide-spread tissue distribution of γδ T cells and their roles in pathogen clearance, immunosurveillance, cancer, and autoimmune diseases. In this review, we will integrate the current understanding of the role of the T cell receptor, environmental signals, and transcription factor networks in controlling mouse innate-like γδ T cell effector commitment.

CCR6− group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6− ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6− ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

Alveolar macrophages (AMs) are the major lung-resident macrophages and have contradictory functions. AMs maintain tolerance and tissue homeostasis, but they also initiate strong inflammatory responses. However, such opposing roles within the AM population were not known to be simultaneously generated and coexist. Here, we uncovered heterogeneous AM subpopulations generated in response to two distinct pulmonary fungal infections, Cryptococcus neoformans and Aspergillus fumigatus Some AMs are bona fide sentinel cells that produce chemoattractant CXCL2, which also serves as a marker for AM heterogeneity, in the context of pulmonary fungal infections. However, other AMs do not produce CXCL2 and other pro-inflammatory molecules. Instead, they highly produce anti-inflammatory molecules, including interleukin-10 (IL-10) and complement component 1q (C1q). These two AM subpopulations have distinct metabolic profiles and phagocytic capacities. We report that polarization of pro-inflammatory and anti-inflammatory AM subpopulations is regulated at both epigenetic and transcriptional levels and that these AM subpopulations are generally highly plastic. Our studies have uncovered the role of C1q expression in programming and sustaining anti-inflammatory AMs. Our finding of the AM heterogeneity upon fungal infections suggests a possible pharmacological intervention target to treat fungal infections by tipping the balance of AM subpopulations.

In the version of this article initially published, the top right plot in Figure 4a was aligned incorrectly. The error has been corrected in the HTML and PDF versions of the article. The original and corrected figures are provided in the accompanying Publisher Correction.

Without novel strategies to prevent mother-to-child HIV-1 transmission, more than 5% of HIV-1-exposed infants will continue to acquire HIV-1, most through breastfeeding. This study of rhesus macaque dam-and-infant pairs is the first preclinical study to investigate the protective role of transplacentally transferred HIV-1 vaccine-elicited antibodies and HIV-1 vaccine-elicited breast milk antibody responses in infant oral virus acquisition. It revealed highly variable placental transfer of potentially protective antibodies and emphasized the importance of pregnancy immunization timing to reach peak antibody levels prior to delivery. While there was no discernible impact of maternal immunization on late infant oral virus acquisition, we observed a strong correlation between the percentage of activated CD4 + T cells in infant peripheral blood and a reduced number of challenges to infection. This finding highlights an important consideration for future studies evaluating alternative strategies to further reduce the vertical HIV-1 transmission risk.