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Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1 hi CD69 hi trNK cells that share transcriptional similarity with CD56 bright TCF1 hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Unlike macrophage networks composed of long-lived tissue-resident cells within specific niches, conventional dendritic cells (cDCs) that generate a 3D network in lymph nodes (LNs) are short lived and continuously replaced by DC precursors (preDCs) from the bone marrow (BM). Here, we examined whether specific anatomical niches exist within which preDCs differentiate toward immature cDCs. In situ photoconversion and Prtn3-based fate-tracking revealed that the LN medullary cords are preferential entry sites for preDCs, serving as specific differentiation niches. Repopulation and fate-tracking approaches demonstrated that the cDC1 network unfolded from the medulla along the vascular tree toward the paracortex. During inflammation, collective maturation and migration of resident cDC1s to the paracortex created discontinuity in the medullary cDC1 network and temporarily impaired responsiveness. The decrease in local cDC1 density resulted in higher Flt3L availability in the medullary niche, which accelerated cDC1 development to restore the network. Thus, the spatiotemporal development of the cDC1 network is locally regulated in dedicated LN niches via sensing of cDC1 densities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

It is generally believed that environmental or cutaneous bacteria are the main origin of surgical infections. Therefore, measures to prevent postoperative infections focus on optimizing hygiene and improving asepsis and antisepsis. In a large cohort of patients with infections following major surgery, we identified that the causative bacteria are mainly of intestinal origin. Postoperative infections of intestinal origin were also found in mice undergoing partial hepatectomy. CCR6 + group 3 innate lymphoid cells (ILC3s) limited systemic bacterial spread. Such bulwark function against host invasion required the production of interleukin-22 (IL-22), which controlled the expression of antimicrobial peptides in hepatocytes, thereby limiting bacterial spread. Using genetic loss-of-function experiments and punctual depletion of ILCs, we demonstrate that the failure to restrict intestinal commensals by ILC3s results in impaired liver regeneration. Our data emphasize the importance of endogenous intestinal bacteria as a source for postoperative infection and indicate ILC3s as potential new targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lymphatic transport of molecules and migration of myeloid cells to lymph nodes (LNs) continuously inform lymphocytes on changes in drained tissues. Here, using LN transplantation, single-cell RNA-seq, spectral flow cytometry, and a transgenic mouse model for photolabeling, we showed that tissue-derived unconventional T cells (UTCs) migrate via the lymphatic route to locally draining LNs. As each tissue harbored a distinct spectrum of UTCs with locally adapted differentiation states and distinct T cell receptor repertoires, every draining LN was thus populated by a distinctive tissue-determined mix of these lymphocytes. By making use of single UTC lineage-deficient mouse models, we found that UTCs functionally cooperated in interconnected units and generated and shaped characteristic innate and adaptive immune responses that differed between LNs that drained distinct tissues. Lymphatic migration of UTCs is, therefore, a key determinant of site-specific immunity initiated in distinct LNs with potential implications for vaccination strategies and immunotherapeutic approaches., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Reinvigoration of exhausted CD8 + T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control. cDC1s were dispensable for Tpex cell expansion but provided an essential niche to promote Tpex cell maintenance, preventing their overactivation and T-cell-mediated immunopathology. Mechanistically, cDC1s insulated Tpex cells via MHC-I-dependent interactions to prevent their activation within other inflammatory environments that further aggravated their exhaustion. Our findings reveal that cDC1s maintain and safeguard Tpex cells within distinct anatomical niches to balance viral control, exhaustion, and immunopathology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Upon viral infection, natural killer (NK) cells expressing certain germline-encoded receptors are selected, expanded, and maintained in an adaptive-like manner. Currently, these are thought to differentiate along a common pathway. However, by fate mapping of single NK cells upon murine cytomegalovirus (MCMV) infection, we identified two distinct NK cell lineages that contributed to adaptive-like responses. One was equivalent to conventional NK (cNK) cells while the other was transcriptionally similar to type 1 innate lymphoid cells (ILC1s). ILC1-like NK cells showed splenic residency and strong cytokine production but also recognized and killed MCMV-infected cells, guided by activating receptor Ly49H. Moreover, they induced clustering of conventional type 1 dendritic cells and facilitated antigen-specific T cell priming early during MCMV infection, which depended on Ly49H and the NK cell-intrinsic expression of transcription factor Batf3. Thereby, ILC1-like NK cells bridge innate and adaptive viral recognition and unite critical features of cNK cells and ILC1s., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Natural killer (NK) cells are innate lymphocytes with the capacity to elicit adaptive features, including clonal expansion and immunological memory. Because signal transducer and activator of transcription 5 (STAT5) is essential for NK cell development, the roles of this transcription factor and its upstream cytokines interleukin-2 (IL-2) and IL-15 during infection have not been carefully investigated. In this study, we investigate how STAT5 regulates transcription during viral infection. We demonstrate that STAT5 is induced in NK cells by IL-12 and STAT4 early after infection and that partial STAT5 deficiency results in a defective capacity of NK cells to generate long-lived memory cells. Furthermore, we find a functional dichotomy of IL-2 and IL-15 signaling outputs during viral infection, whereby both cytokines drive clonal expansion, but only IL-15 is required for memory NK cell survival. We thus highlight a role for STAT5 signaling in promoting an optimal anti-viral NK cell response., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1 + ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1 + ST2 - ILCPs to Il18r - ST2 + ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

T cell homeostasis critically depends on interleukin-7 (IL-7). In this issue of Immunity, Martin et al. (2017) provide evidence that IL-7 availability is regulated through a "cytokine sink" involving innate lymphoid cells that compete for and consume IL-7 and thereby restrict T cell homeostasis in lymphoid organs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3' UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction. Our data suggest that the role of a single miRNA-mRNA interaction is dependent on cell type and biological context., (Copyright © 2015 Elsevier Inc. All rights reserved.)

T lymphocytes’ ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However, recent studies have suggested that the output of this discrimination process is conditioned by environmental cues. Here, we demonstrate how the IL-2 cytokine, collectively generated by strongly activated T cell clones, can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues, including local cues such as antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines.

In multicellular organisms, specialized functions are delegated to distinct cell types whose identity and functional integrity are maintained upon challenge. However, little is known about the mechanisms enabling lineage inheritance and their biological implications. Regulatory T (Treg) cells, which express the transcription factor Foxp3, suppress fatal autoimmunity throughout the lifespan of animals. Here, we show that a dedicated Foxp3 intronic element CNS2 maintains Treg cell lineage identity by acting as a sensor of the essential Treg cell growth factor IL-2 and its downstream target STAT5. CNS2 sustains Foxp3 expression during division of mature Treg cells when IL-2 is limiting and counteracts proinflammatory cytokine signaling that leads to the loss of Foxp3. CNS2-mediated stable inheritance of Foxp3 expression is critical for adequate suppression of diverse types of chronic inflammation by Treg cells and prevents their differentiation into inflammatory effector cells. The described mechanism may represent a general principle of the inheritance of differentiated cell states., (Copyright © 2014 Elsevier Inc. All rights reserved.)