Sepsis induced dysfunction of liver type 1 innate lymphoid cells.

Sepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood. This study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells. Sepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis.

Wang P ，Zheng Y ，Sun J ，Zhang Y ，Chan WK ，Lu Y ，Li X ，Yang Z ，Wang Y ... -  《BMC IMMUNOLOGY》

Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s.

Group 1 innate lymphoid cells (ILCs) consist of conventional natural killer (cNK) cells, tissue-resident NK cells and mucosal ILC1s. Recently identified liver-resident NK cells, which can mount contact hypersensitivity responses, and mucosal ILC1s that are involved in pathogenesis of colitis are distinct from cNK cells in several aspects, but the issue of how they are related to each other has not been clearly clarified. Here, we show that liver-resident NK cells and mucosal ILC1s have different phenotypes, as evidenced by distinct expression patterns of homing-associated molecules. Moreover, mucosal ILC1s exhibit tissue residency akin to liver-resident NK cells. Importantly, liver-resident NK cells express relative high levels of cytotoxic effector molecules, which are poorly expressed by mucosal ILC1s, and exhibit stronger cytotoxic activity compared with mucosal ILC1s. These results demonstrate differential phenotypic and functional characteristics of liver-resident NK cells and mucosal ILC1s, shedding new light on the diversity of ILC family.

Tang L ，Peng H ，Zhou J ，Chen Y ，Wei H ，Sun R ，Yokoyama WM ，Tian Z ... -  《-》

Prdm1 positively regulates liver Group 1 ILCs cancer immune surveillance and preserves functional heterogeneity.

Group 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and type 1 innate lymphoid cells (ILC1s). The main functions of liver cNK cells and ILC1s not only include directly killing target cells but also regulating local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of liver cNK cells and ILC1s, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role of Prdm1 in shaping the composition and maturation of cNK cells. Although Prdm1 did not affect the killing function of cNK cells in an in vivo cytotoxicity model, a significant increase in cancer metastasis was observed in Prdm1 knockout mice. Interferon-gamma (IFN-γ), granzyme B, and perforin secretion decreased significantly in Prdm1-deficient cNK cells and liver ILC1s. Single-cell RNA sequencing (scRNA-seq) data also provided evidences that Prdm1 maintains functional subsets of cNK cells and liver ILC1s and facilitates communications between cNK cells, liver ILC1s, and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in cNK cells and liver ILC1s, showing promising potential for developing innovative immune therapy strategies against liver cancer.

He J ，Gao L ，Wang P ，Chan WK ，Zheng Y ，Zhang Y ，Sun J ，Li X ，Wang J ，Li XH ，Chen H ，Yang Z ，Wang Y ... -  《eLife》

Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches.

Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodal in vivo approaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7 R- ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7 R- ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7 R- ILC1s. IL-7R+ (7R+) ILC1s in the liver, candidate precursors for 7 R- ILC1s, are not essential for 7 R- ILC1 development in physiological conditions. Functionally, 7 R- ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.

Asahi T ，Abe S ，Cui G ，Shimba A ，Nabekura T ，Miyachi H ，Kitano S ，Ohira K ，Dijkstra JM ，Miyazaki M ，Shibuya A ，Ohno H ，Ikuta K ... -  《eLife》

Type 1 innate lymphoid cells: Soldiers at the front line of immunity.

Innate lymphoid cells (ILCs) are tissue-resident innate lymphocytes that have functions to protect the hosts against pathogens and that regulate tissue inflammation and homeostasis. ILC subsets rapidly produce particular cytokines in response to infection, inflammation, and tissue injury at the local environment. Type 1 ILCs (ILC1s) promptly and abundantly produce interferon (IFN)-γ but lack appreciable cytotoxic activity. ILC1s share many phenotypic, developmental, and functional characteristics with natural killer (NK) cells, which are circulating innate lymphocytes with potent natural cytotoxicity. However, recent studies have established ILC1s as distinct from NK cells. ILC1s predominantly reside in the liver-they initially were discovered as a liver-resident ILC subset-as well as in other lymphoid and non-lymphoid tissues. Accumulating evidence has demonstrated that ILC1s play an important and unique role in host protection and in immunomodulation in their resident organs. However, the pathophysiological role of tissue-resident ILC1s remains largely unclear. In this review, we summarize emerging evidence showing that ILC1s not only contribute to inflammation to protect against pathogens but also promote tissue protection and metabolism. We highlight a unique function of ILC1s in their resident tissues.

Nabekura T ，Shibuya A 《-》