Biology subjects

Yokoyama, W. M.

Publications and source records attributed to Yokoyama, W. M..

8 recordsLinked to original sources

bioRxiv2026

CD8+ T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration

There are changes in adaptive immunity in Alzheimers disease (AD) and increases in activated CD8+ T cells in brain correlate with tau pathology1-3. However, which cells mediate T cell priming in tau-mediated neurodegeneration remains unclear. In different conditions such as cancer, viral infections, and autoimmune diseases outside the CNS, conventional type-1 dendritic cells (cDC1) perform antigen cross-presentation to prime CD8+ T cells4,5. We demonstrate that tauopathy mice deficient in cDC1 are markedly protected against tau-mediated neurodegeneration and display a selective decrease in brain CD8+ T cell infiltration and glial reactivity. The remaining CD8+ T cells showed an antigen inexperienced status with less clonal expansion, indicating suboptimal T cell priming. We confirm that brain derived antigens are presented in secondary lymphoid tissues to prime CD8+ T cells. Our study identifies cDC1 cells as critical for CD8+ T cell priming outside the CNS. This priming is required for a large increase of activated CD8+ T cells in the brain which promotes tau-mediated neurodegeneration.

neuroscience↗

bioRxiv2025

TGF-β drives the conversion of conventional NK cells into uterine tissue-resident NK cells to support murine pregnancy

Tissue microenvironments shape lymphocyte differentiation to align immune function with local physiological demands. Uterine natural killer cells are critical for reproductive success, yet the molecular cues in the uterus that instruct their specialized identities remain incompletely understood. Here, we identify a TGF-{beta}-dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-{beta} receptor II expression in Ncr1-expressing cells disrupted this conversion, markedly reducing tissue-resident NK cells in the gravid uterus. Impaired TGF-{beta}-driven uterine tissue-resident NK cell differentiation during murine pregnancy led to abnormal spiral artery remodeling and increased fetal resorption rates at midgestation, ultimately reducing litter sizes at birth. Collectively, these findings define TGF-{beta} as a pivotal driver of tissue-resident NK cell differentiation in the gravid uterus and establish a mechanistic framework through which the uterine microenvironment programs NK cell identity to meet the physiological demands of gestation.

immunology↗

bioRxiv2025

Eomesodermin defines uterine NK cells crucial for pregnancy success in mice

Uterine natural killer cells have been thought to be critical for reproductive success, and their developmental origins remain unclear. Here, we demonstrate that Eomesodermin is a key transcription factor determining the lineage of tissue-resident NK cells within the uterus both at steady-state and during pregnancy. Ablation of Eomesodermin in Ncr1-expressing cells results in the loss of tissue-resident NK cells in both the virgin and pregnant uterus, suggesting that uterine tissue-resident NK cells derive from precursors in the conventional NK cell lineage. We further show that the genetic absence of uterine NK cells during murine gestation leads to adverse pregnancy outcomes marked by reduced litter sizes and increased resorption rates. Collectively, our data underscore the pivotal role of uNK cells in pregnancy and offer novel insights into their lineage specification, revealing Eomesodermin as a crucial factor in their establishment.

immunology↗

bioRxiv2024

Expression of a single inhibitory Ly49 receptor is sufficient to license NK cells for effector functions

Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of MHC class I and related molecules. Functionally, these receptor families are involved in licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on a H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.

immunology↗

bioRxiv2022

The Transcription Factor Bach2 Negatively Regulates Natural Killer Cell Maturation and Function

BTB domain And CNC Homolog 2 (Bach2) is a transcription repressor that actively participates in T and B lymphocyte development, but it is unknown if Bach2 is also involved in the development of innate immune cells, such as natural killer (NK) cells. Here, we followed the expression of Bach2 during NK cell development, finding that it peaked in CD27+CD11b+ cells and decreased upon further maturation. Bach2 expression positively correlated with that of the transcription factor TCF1 and negatively correlated with genes encoding NK effector molecules as well as genes involved in the cell cycle. Bach2-deficient mice showed increased numbers of terminally differentiated NK cells with increased production of granzymes and cytokines. NK cell-mediated control of tumor metastasis was also augmented in the absence of Bach2. Therefore, Bach2 is a key checkpoint protein regulating NK terminal maturation.

immunology↗

bioRxiv2021

NK cell metabolic adaptation to infection promotes survival and viral clearance.

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1 (HIF-1) is a feature of NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1 KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF1-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF1-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

immunology↗

bioRxiv2020

Virus infection is controlled by cell type-specific sensing of murine cytomegalovirus through MyD88 and STING

Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through patternrecognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we investigated anti-viral effects of MyD88 and STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to MyD88. However, unlike MyD88, STING also contributed to viral control in non-hematological, stromal cells. Infected splenic stromal cells produced IFN-I in a cGAS-STING-dependent and MyD88-independent manner, while plasmacytoid dendritic cell IFN-I had inverse requirements. MCMV-induced natural killer (NK) cytotoxicity was dependent on MyD88 and STING. Thus, MyD88 and STING contribute to MCMV control in distinct cell types that initiate downstream immune responses.

immunology↗

bioRxiv2019

Toxoplasma gondii infection drives conversion of NK Cells into ILC1s

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describe Toxoplasma gondii infection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes- Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

immunology↗