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Wayne M Yokoyama

Publications and source records attributed to Wayne M Yokoyama.

At least 19 recordsLinked to original sources
PubMed2026

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.

Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.

Journal Article↗
PubMed2006

IL-18 acts synergistically with IL-15 in stimulating natural killer cell proliferation.

Mature natural killer (NK) cells are able to vigorously proliferate in response to infectious stimuli such as viral infections. The factors driving NK cell proliferation under these circumstances are only beginning to be characterized. NK cells constitutively express interleukin-18 receptor alpha and are stimulated by IL-18 to produce IFNgamma. Although IL-18 alone is not sufficient to drive NK cell proliferation, we demonstrate that IL-18 is able to act synergistically with IL-15 in stimulating in vitro NK cell proliferation. Furthermore using a NK cell line, we show that this effect occurs through direct stimulation of NK cells by IL-18 rather than through a secondary signal generated by an intermediary cell type. This raises the possibility that IL-18 may act synergistically with IL-15 in driving pathogen-induced NK cell proliferation in addition to its contribution in enhancing IL-12 stimulation of NK cell IFNgamma production.

Animals↗
PubMed2006

DAP12 signaling directly augments proproliferative cytokine stimulation of NK cells during viral infections.

NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.

Adaptor Proteins, Signal Transducing↗
PubMed2006

NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1 expression on the tumor cells for optimal perforin-dependent effector function.

The NKG2D receptor on NK cells can recognize a variety of ligands on the tumor cell surface. Using a mouse renal cancer (Renca), we show that NKG2D recognition by NK cells was crucial for their ability to limit tumor metastases in vivo in both liver and lungs using perforin-dependent effector mechanisms. However, for the R331 cell line established from Renca, NKG2D recognition and perforin-dependent lysis played no role in controlling liver metastases. R331 cells were also more resistant to perforin-dependent lysis by NK cells in vitro. We therefore used these phenotypic differences between Renca and R331 to further investigate the crucial receptor:ligand interactions required for triggering lytic effector functions of NK cells. Reconstitution of R331 cells with ICAM-1, but not Rae-1gamma, restored NKG2D-mediated, perforin-dependent lysis. Interestingly, R331 cells were efficiently lysed by NK cells using death ligand-mediated apoptosis. This death ligand-mediated killing did not depend on NKG2D recognition of its ligands on tumor cells. This result suggests that the intracellular signaling in NK cells required for perforin and death ligand-mediated lysis of tumor target cell are quite distinct, and activation of both of these antitumor lytic effector functions of NK cells could improve therapeutic benefits for certain tumors.

Animals↗
PubMed2006

IFN-dependent down-regulation of the NKG2D ligand H60 on tumors.

In this study, we show that IFN-gamma or IFN-alpha reduce expression of H60 on 3'-methylcholanthrene (MCA) sarcomas from 129/Sv mice. As determined by flow cytometry using either NKG2D tetramers or NKG2D ligand-specific mAb, H60 was identified as the NKG2D ligand most frequently expressed on these sarcomas, and its expression was selectively down-regulated by either IFN-gamma or IFN-alpha in a manner that was dose- and time-dependent and reversible. Down-regulation occurred at the transcript level and was STAT1-dependent. It also had functional consequences. IFN-gamma-treated MCA sarcomas with high levels of H60 were resistant to killing by IL-2-activated NK cells. Resistance was not solely dependent on enhanced MHC class I expression but rather also required H60 down-regulation. IFN-gamma-treated tumor cells also displayed diminished capacity to down-regulate NKG2D on freshly isolated NK cells. Transplanted tumor cells reisolated from immunocompetent mice displayed reduced H60 expression and increased MHC class I expression compared with tumor cells that were either left unmanipulated or reisolated from mice treated with neutralizing IFN-gamma-specific mAb. This report thus represents the first demonstration that certain cytokines and specifically the IFNs regulate expression of specific NKG2D ligands on murine tumors. This process most likely helps to specify the type of immune effector cell populations that participate in host-protective antitumor responses.

Animals↗
PubMed2006

How do natural killer cells find self to achieve tolerance?

Natural killer (NK) cells provide innate defense against tumors and infections by virtue of potent capacities to immediately kill cellular targets and produce cytokines. These effector functions may potentially damage normal self-tissues unless they are kept in check by tolerance mechanisms that need clarification. Here, we discuss recent studies indicating that the NK cells acquire functional competence directly through engagement of their MHC-specific receptors by self-MHC. Ironically, these receptors were first identified in terms of recognizing target cell MHC class I molecules and inhibiting NK cells in effector responses. Other studies of NK cell tolerance are also discussed. Although these studies begin to clarify the means by which NK cell tolerance is achieved, much more investigation is needed because NK cell tolerance is relevant to clinical observations in patients with infections and cancer.

Animals↗
PubMed2006

Licensing of natural killer cells by self-major histocompatibility complex class I.

Natural killer (NK) cells have potent capacities to immediately kill cellular targets and produce cytokines that may potentially damage normal self-tissues unless they are kept in check. Such tolerance mechanisms are incompletely understood. Here we discuss recent studies suggesting that NK cells undergo a host major histocompatibility complex (MHC) class I-dependent functional maturation process, termed 'licensing'. Ironically, licensing directly involves inhibitory receptors that recognize target cell MHC class I molecules and block activation of NK cells in effector responses. This process results in two types of tolerant NK cells: functionally competent (licensed) NK cells, whose effector responses are inhibited by self-MHC class I molecules through the same receptors that conferred licensing, and functionally incompetent (unlicensed) NK cells.

Animals↗
PubMed2006

Expression of m157, a murine cytomegalovirus-encoded putative major histocompatibility class I (MHC-I)-like protein, is independent of viral regulation of host MHC-I.

A murine cytomegalovirus (MCMV)-encoded protein, m157, has a putative major histocompatibility complex class I (MHC-I) structure and is recognized by the Ly49H NK cell activation receptor. Using a monoclonal antibody against m157, in this study we directly demonstrated that m157 is a cell surface-expressed glycophosphatidylinositol-anchored protein with early viral gene kinetics. Beta-2 microglobulin and TAP1 (transporter associated with antigen processing 1) were not required for its expression. MCMV-encoded proteins that down-regulate MHC-I did not affect the expression of m157. Thus, m157 is expressed on infected cells in a manner independent of viral regulation of host MHC-I.

Animals↗
PubMed2005

Arrested natural killer cell development associated with transgene insertion into the Atf2 locus.

Natural killer (NK) cell development in the bone marrow is not fully understood. Following lineage commitment, these cells appear to advance through a series of developmental stages that are beginning to be characterized. We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1-specific inhibitory receptor driven by the granzyme A gene. This mouse has few NK cells in peripheral tissues with relative preservation of other immune cells, including T and B cells. Herein we demonstrate that these mice have an accumulation of NK cells with an immature phenotype in the bone marrow, consistent with a block at a previously proposed stage in normal NK-cell development. The phenotype is associated with transgenic insertion into Atf2, the gene for the basic leucine zipper (bZIP) transcription factor family member ATF-2. Although analysis of Atf2-null NK cells shows no defect, the transgenic mice express abnormal truncated Atf2 transcripts that may mediate a repressor effect because ATF2 can heterodimerize with other bZIP molecules. The defect is cell intrinsic, suggesting that certain bZIP molecules play significant roles in NK-cell development.

Activating Transcription Factor 2↗
PubMed2005

Costimulation through NKG2D enhances murine CD8+ CTL function: similarities and differences between NKG2D and CD28 costimulation.

Multiple studies have demonstrated that the NK cell activating receptor NKG2D can function as a costimulatory receptor for both mouse and human CD8+ T cells. However, it has recently been suggested that stimulation through NKG2D is insufficient for costimulation of CD8+ T cells. To aid in the delineation of NKG2D function in CTL responses, we investigated whether stimulation of NKG2D by the natural ligand RAE1epsilon was able to costimulate effector functions of a murine CTL line generated from DUC18 TCR transgenic mice. We found that NKG2D was able to costimulate DUC CTL responses and did so in a manner similar to CD28 costimulation. The T cells exhibited increased proliferation, IFN-gamma release, and cytotoxicity when presented antigenic peptide by P815 cells expressing RAE1epsilon or B7-1 compared with untransfected P815. In addition, both RAE1epsilon and B7-1 enhanced Ag-independent IFN-gamma secretion in response to IL-12 and IL-18 by DUC CTL. However, only costimulation through CD28 allowed for DUC CTL survival upon secondary stimulation, whereas ligation of NKG2D, but not CD28, induced DUC CTL to form an immune synapse with target cells in the absence of TCR stimulation. Understanding the outcomes of these differences may allow for a better understanding of T cell costimulation in general.

Animals↗
PubMed2005

NKG2D function protects the host from tumor initiation.

The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-gamma or tumor necrosis factor-related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1(+) and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.

Animals↗
PubMed2005

NKG2D-independent suppression of T cell proliferation by H60 and MICA.

The activating receptor NKG2D recognizes a wide range of different ligands, some of which are primarily expressed in "stressed" tissues or on tumor cells. Until now, similar stimulatory effects on natural killer and CD8+ T cells have been described for all NKG2D ligands, and the NKG2D receptor/ligand system has therefore been interpreted as a sensor system involved in tumor immune surveillance and activation of immune responses. We show here that the NKG2D ligands H60 and MIC class 1 chain-related protein A (MICA) can also mediate strong suppressive effects on T cell proliferation. Responsiveness to H60- and MICA-mediated suppression requires IL-10 and involves a receptor other than NKG2D. These findings might provide explanations for the observation that strong in vivo NKG2D ligand expression, such as that on tumor cells, sometimes fails to support effective immune responses and links this observation to a distinct subgroup of NKG2D ligands.

Animals↗
PubMed2005

Licensing of natural killer cells by host major histocompatibility complex class I molecules.

Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.

Animals↗
PubMed2005

Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo.

The immunoreceptor NKG2D stimulates activation of cytotoxic lymphocytes upon engagement with MHC class I-related NKG2D ligands of which at least some are expressed inducibly upon exposure to carcinogens, cell stress, or viruses. In this study, we investigated consequences of a persistent NKG2D ligand expression in vivo by using transgenic mice expressing MHC class I chain-related protein A (MICA) under control of the H2-K(b) promoter. Although MICA functions as a potent activating ligand of mouse NKG2D, H2-K(b)-MICA mice appear healthy without aberrations in lymphocyte subsets. However, NKG2D-mediated cytotoxicity of H2-K(b)-MICA NK cells is severely impaired in vitro and in vivo. This deficiency concurs with a pronounced down-regulation of surface NKG2D that is also seen on activated CD8 T cells. As a consequence, H2-K(b)-MICA mice fail to reject MICA-expressing tumors and to mount normal CD8 T cell responses upon Listeria infection emphasizing the importance of NKG2D in immunity against tumors and intracellular infectious agents.

Animals↗
PubMed2005

Phospholipase C-gamma 2 is a critical signaling mediator for murine NK cell activating receptors.

Phospholipase C-gamma (PLCgamma) is a key regulator of intracellular Ca(2+) mobilization. Two isoforms of PLCgamma have been identified, PLCgamma1 and PLCgamma2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLCgamma2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLCgamma2 is more important than PLCgamma1 for NK cell activation and whether PLCgamma2 is also critical for NK cell development, secretion of IFN-gamma, and clearance of viral infections in vivo is not known. In this study, we report that PLCgamma2 is the predominant isoform expressed in murine NK cells. PLCgamma2 deficiency did not affect NK cell numbers in bone marrow and spleen, but acquisition of Ly49 receptors by NK cells was partially impaired. PLCgamma2-deficient NK cells exhibited a dramatic impairment of cytolytic function and IFN-gamma production upon ligation of activating receptors, whereas they did secrete IFN-gamma in response to cytokines. Consequently, mice lacking PLCgamma2 controlled murine CMV infection substantially less effectively than did wild-type animals, and this defect was most evident in the spleen, where viral clearance mostly depends on NK cell lytic function. These results demonstrate that PLCgamma2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo.

Adaptor Proteins, Signal Transducing↗