The Dynamics of Dendritic Cell—Mediated Innate Immune Regulation

ABSTRACTAfter taking up pathogen-derived antigens, dendritic cells (DCs) leave peripheral organs and migrate into sentinel lymph nodes via afferent lymphatic vessels. During this process, they undergo maturation and produce proinflammatory cytokines, which leads to efficient antigen (Ag) presentation and activation of the innate and acquired immune systems. Recent evidence indicates that DC subsets cooperate to activate the innate immune system. It is becoming clear that the total DC population is composed of a network of DC subsets with distinct functions that are critical for sensing pathogens and orchestrating immune responses

The Transcription Factor NF-ATc1 Regulates Lymphocyte Proliferation and Th2 Cytokine Production

AbstractNF-ATc1 is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In activated T cells, nuclear NF-AT binds to the promoter regions of multiple cytokine genes and induces their transcription. The role of NF-ATc1 was investigated in recombination activating gene-1 (RAG-1)–deficient blastocyst complementation assays using homozygous NF-ATc1−/− mutant ES cell lines. NF-ATc1−/−/RAG-1−/− chimeric mice showed reduced numbers of thymocytes and impaired proliferation of peripheral lymphocytes, but normal production of IL-2. Induction in vitro of Th2 responses, as demonstrated by a decrease in IL-4 and IL-6 production, was impaired in mutant T cells. These data indicate that NF-ATc1 plays roles in the development of T lymphocytes and in the differentiation of the Th2 response

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow

骨髄のNK細胞の分化に造血細胞が産生するIL-15が必須である --2種類の局在を示すNK細胞の新規分化モデル--. 京都大学プレスリリース. 2023-09-20.Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

新規の循環型iNKT細胞を発見 --抗腫瘍・抗ウイルス感染効果の高い免疫細胞療法の開発への貢献に期待--. 京都大学プレスリリース. 2022-10-24.Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244⁻CXCR6⁻), C1 (CD244⁻CXCR6⁺), or C2 (CD244⁺CXCR6⁺) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244⁺CXCR6⁺ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells

The Dynamics of Dendritic Cell—Mediated Innate Immune Regulation

After taking up pathogen-derived antigens, dendritic cells (DCs) leave peripheral organs and migrate into sentinel lymph nodes via afferent lymphatic vessels. During this process, they undergo maturation and produce proinflammatory cytokines, which leads to efficient antigen (Ag) presentation and activation of the innate and acquired immune systems. Recent evidence indicates that DC subsets cooperate to activate the innate immune system. It is becoming clear that the total DC population is composed of a network of DC subsets with distinct functions that are critical for sensing pathogens and orchestrating immune responses

Monopoiesis in humans and mice

Monocytes are a widely conserved cell population in vertebrates with important roles in both inflammation and homeostasis. Under both settings, monocytes continuously arise from hematopoietic progenitors in the bone marrow and, on demand, migrate into tissues through the bloodstream. Monocytes are classified into three subsets—classical, intermediate and non-classical—based on their cell surface expression of CD14 and CD16 in humans and Ly6C, CX3CR1 and CCR2 in mice. In tissues, monocytes differentiate further into monocyte-derived macrophages and dendritic cells to mediate innate and adaptive immune responses and maintain tissue homeostasis. Recently, the progenitors that strictly give rise to monocytes were identified in both humans and mice, thereby revealing the monocyte differentiation pathways.ISSN:0953-8178ISSN:1460-237