Fumio Takei


Relevant Thesis-Based Degree Programs


Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Development and heterogeneity of type 2 innate lymphoid cells in mouse lungs (2020)

Lung group 2 innate lymphoid cells (ILC2s) drive allergic inflammation and promote tissue repair. To investigate the early developmental pathways that leads to the generation of lung ILC2, I divided adult bone marrow lymphoid primed multipotent progenitor (LMPPs) into CD127⁻ (LMPP-s) and CD127⁺ (LMPP+s) subsets and compared them with Ly6D⁻ and Ly6D⁺ common lymphoid progenitors (CLPs). Although, all lymphocytes are thought to develop from CLPs, LMPP+s differentiated into T cells and ILCs more rapidly and efficiently than other progenitors in transplantation assays. These results suggested that some ILCs and T cells may develop from LMPP+s via CLP-independent pathways. To investigate whether distinct ILC2 subsets mediate the distinct ILC2 functions and elucidate their developmental relationship, we generated RORα lineage tracer mice and analyzed them by single cell RNA sequencing, flow cytometry and functional assays. Adult lung ILC2s were divided into IL-18Rα⁺ST2⁻ and IL-18Rα⁻ST2⁺ subsets. The former had an immature ILC phenotype, produced little cytokines and contained ILC progenitor like cells expressing Tcf7, whereas the latter was conventional ILC2s. Neonatal lung conventional ILC2s (IL-18Rα⁻ST2⁺) were divided into two distinct effector subsets and an IL-18Rα⁺ST2⁻Tcf7⁺ progenitor-like subset. The two effector subsets were defined by the expression of ICOS and KLRG1, and they differentially produced the growth-factor amphiregulin and type 2 cytokines. Therefore, effector ILC2s diverge into tissue-repairing and pro-inflammatory subsets, which differ in transcriptional and phenotypic properties. The IL-18Rα⁺ST2⁻Tcf7⁺ cells are likely IL-18 responsive lung ILC progenitors, which may contribute to ILC-poiesis in neonatal and inflamed lungs.

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Tissue resident and migratory group 2 innate lymphoid cells in mice (2020)

Group 2 innate lymphoid cells (ILC2s) primarily reside on mucosal surfaces and produce copious amounts of IL-5 and IL-13 upon activation by epithelium-derived cytokines, such as IL-33, leading to inflammation characterized by eosinophilia. Elevated numbers of ILC2s are found in the peripheral blood of patients with allergic diseases including asthma, suggesting their involvement in the disease. Epidemiological studies have shown higher prevalence of asthma in women than men during reproductive age, but the mechanism is largely unknown. By using flow cytometric analyses, I found that post-pubertal female lung ILC2s are more responsive to IL-33 stimulation than male ILC2s. Gene expression analyses of purified ILC2s and measurement of epithelium-derived cytokines in the lung demonstrated ILC2 intrinsic and lung environmental differences between naïve female and male lungs, suggesting a more activated state of female ILC2s compared to male ILC2s at steady state conditions.ILC2s have previously been shown to be tissue resident at steady state as well as during inflammation. However, recent reports have demonstrated migratory potential of ILC2s upon activation. Intranasal IL-33 administration into mice caused expansion of ILC2s not only in the lung but also in the blood and liver. Parabiosis experiments showed that ILC2s migrate out of the lung to the liver through circulation. Lung-derived ILC2s potently produced IL-5, IL-13 and IL-6, inducing eosinophilia and mild fibrosis. In contrast, intranasal IL-33 pre-treatment attenuated concanavalin A-induced acute hepatitis and cirrhosis.Overall, these results highlight the complexity of ILC2 regulation and ILC2-mediated local and systemic immunity. These considerations need to be taken into account when investigating ILC2s in human diseases.

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Neonatal lung group 2 innate lymphoid cells and their role in mediating type 2 immunity and allergen sensitization (2019)

Airway allergic diseases predominantly originate from early life exposure to allergens, but the mechanism behind this is unclear. Group 2 innate lymphoid cells (ILC2s) are critical for innate and adaptive immune responses to airway allergens in adult mice. Therefore, I hypothesized that ILC2s play an essential role in neonatal lung immunity. ILC2s quickly seed the mouse lung after birth and begin proliferating and producing IL-13 and IL-5 around postnatal day 10-14, inducing eosinophilia. Neonatal pups deficient for IL-33, an epithelial-derived alarmin that activates ILC2s, have fewer lung ILC2s and eosinophils at day 10 than wildtype (WT) pups. The amount of IL-33 in WT pups is high at day 10 and decreases after day 15, correlating with a contraction of ILC2s into adulthood. Thus, spontaneous release of IL-33 into neonatal lungs provokes activation of ILC2s and eosinophilia. Neonatal ILC2s are more responsive to intranasal (I.N) protease allergen papain than adult ILC2s and respond more intensely upon a secondary challenge in adulthood. Furthermore, ILC2s drive neonatal Th2-biased cell differentiation. I.N OVA antigen treatments into day 10 ILC2-deficient pups transplanted with OT-II adult CD4⁺ T cells results in fewer IL-4⁺IL-13⁺ CD4⁺ OT-II T cells in the lung-draining lymph node than in WT pups. Therefore, ILC2s play a role in neonatal sensitization to allergens leading to persistent allergic disease. The majority of neonatal ILC2s incorporate BrdU, and the BrdU-labeled neonatal ILC2s persist into adulthood, comprising almost 30% of adult lung ILC2s. To determine the effect of neonatal IL-33 exposure on ILC2 function, I.N IL-33 was given to IL-33-deficient (KO) and wildtype (WT) adult mice. While there was no difference in the number of lung ILC2s, there were fewer IL-5⁺IL-13⁺ ILC2s in IL-33KO than IL-33WT mice. I.N IL-33 into IL-33KO pups rescued the impaired response in adulthood. Microarray analysis showed cell-intrinsic differences between IL-33KO and IL-33WT ILC2s. Overall, weak activation by endogenous IL-33 of neonatal lung ILC2s may “train” ILC2s to respond strongly to allergen exposure later in life. These results place ILC2s as crucial components of neonatal lung immunity and should be taken into consideration when developing therapeutics for the prevention of allergic disease development.

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Natural helper celll development and their role in mediating the innate Th2 inflammatory response (2013)

No abstract available.

B cells as regulators of natural killer IFN-gamma production in mice (2011)

No abstract available.

The role of talin in LFA-1 function in cell-mediated cytotoxicity (2010)

No abstract available.

Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Common lymphoid progenitor independent pathways of innate and lymphocyte development (2015)

All lymphocytes are thought to develop from a single population of committed lymphoid progenitors termed common lymphoid progenitors (CLPs). However, upstream progenitors termed lymphoid-primed multi-potent progenitors (LMPPs) are known to be more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s), suggesting alternative pathways of their development. Here, we have divided LMPPs into CD127- (LMPP-s) and CD127+ (LMPP+s) subsets and compared them with CLPs. Adult LMPP+s are the most efficient progenitors for T cells and ILCs in transplantation assays, and lineage tracking by the recombinase expression also suggests that most ILC2s and NK cells develop from LMPPs independent of CLPs. In the neonatal period CLPs are rare and, unlike prominent neonatal LMPP+s, incapable of differentiating into ILC2s and T cells while their development is highly active. These results suggest non-linear pathways of innate and T lymphocyte development from LMPP+s with limited CLP contributions.

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A more efficient killing machine: how CpG-oligodeoxynucleotides enhance natural killer cellcytokine production and cytotoxicity against leukemia initiating cells (2012)

Natural killer (NK) cells are lymphocytes that comprise part of the innate immune system and play a key role in the early defence against pathogenic organisms and cancer. CpG oligodeoxynucelotides (ODNs) are short synthetic ODN containing unmethylated CpG dinucleotide motifs that have immune-enhancing effects. NK cell-derived IFN-γ is essential for the effects of CpG ODNs, but how NK cells become activated by CpG ODNs remains unclear. We found that CpG ODN-mediated stimulation of NK cells requires IL-12 or IL-18. CpG ODNs did not stimulate IL-12-deficient mouse spleen cells and IL-12 neutralization almost completely inhibited IFN-γ production. Although IL-18 was undetectable in cultures, neutralization significantly dampened the IFN-γ response and addition of exogenous IL-18 greatly enhanced CpG ODN-mediated NK cell stimulation. IL-12 is mainly produced by Gr-1⁺ monocytes and neutrophils, while what cells produce IL-18 remains unknown. We then tested the anti-leukemia effects of CpG ODN-stimulated NK cells. Studies with human acute myeloid leukemia (AML) patients have shown that haploidentical NK cells effectively kill AML blasts, but their ability to lyse leukemia initiating cells (LICs) has not been studied. Therefore, we tested NK cells from haploidentical F1 mice against the mouse AML cell line MN1. F1 mouse NK cells expanded in cultures in the presence of IL-15 and stimulated by CpG ODNs plus IL-18, effectively killed bulk MN1 cells in vitro and reduced the numbers of in vitro colony forming cells. NK cell-treated MN1 cells were also injected into irradiated B6 mice to test whether AML LICs were also killed. F1 mouse NK cells seemed to kill some AML initiating cells since mice receiving NK-treated MN1 cells survived significantly longer than those given untreated MN1 cells, but the frequency of LICs did not significantly differ between MN1 cells incubated with or without NK cells. For NK cells to be used as a treatment for AML, we must find a way to induce a higher cytotoxicity in NK cells or to target them specifically towards LIC.

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