PubMed Health⌕ Search

Biomedical subjects

H G Ljunggren

Publications and source records attributed to H G Ljunggren.

At least 55 records · Page 3Linked to original sources
PubMed1999

Triggering of murine NK cells by CD40 and CD86 (B7-2).

NK cell-mediated cytotoxicity is regulated by both triggering and inhibitory signals. The interaction between MHC class I molecules expressed on target cells and specific MHC class I-binding receptors expressed by NK cells generally leads to inhibition of lysis. We have shown recently that CD80 (B7-1) in mice and CD40 in humans trigger NK cell-mediated cytotoxicity in vitro. In the present study, we show that murine CD40 and CD86 (B7-2) trigger murine NK cell-mediated cytotoxicity in vitro when expressed on tumor cells. Preincubation of the transfected cell lines with anti-CD40 F(ab')2 fragments or cytolytic T lymphocyte-associated Ag-4-Ig (CTLA-4-Ig) before the cytotoxic assay abolished the triggering effect. Furthermore, radiolabeled CD40- and B7-2-expressing cells were rapidly eliminated in vivo in an NK cell-dependent manner. NK cells from CD40 ligand (CD40L)-/- or CD28-/- mice were triggered by tumor cells transfected with CD40 and B7-2, respectively, and these transfectants were rapidly eliminated in vivo when inoculated into CD40L-/- and CD28-/- mice. This suggests that the CD40 and B7-2 molecules can interact with receptors on NK cells other than CD40L and CD28, respectively, and that these may account for some of the reactivities observed in the present study. Collectively, these data demonstrate that 1) costimulatory molecules, other than B7-1, can modulate NK cell responses in vitro, 2) they can also affect NK cell-dependent responses in vivo, and 3) parts of these reactions are independent of CD28 and CD40L.

Animals↗
PubMed1999

Induction of experimental autoimmune neuritis in CD4-8-C57BL/6J mice.

The C57BL/6J mice strain is known to be reputedly resistant to induction of experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in humans. Here we describe the induction of EAN in mice of the C57BL/6J background by transfer into naive syngeneic recipients bovine peripheral nerve myelin (BPM)-primed donor lymph node cells that had been stimulated in vitro with the bovine peripheral nervous system (PNS) myelin P2 protein peptide 57-81 followed by challenge with BPM, Freund's complete adjuvant and pertussis toxin. EAN was more severe, both clinically and histologically, and accompanied by extensive infiltration of inflammatory cells and demyelination in peripheral nerves when examined on day 30 after transfer of primed T cells from CD4- 8- mice into identical naive hosts than after transfer of cells from primed wild type, CD4-/- or CD8-/- mice to corresponding recipient animals. EAN in CD4-8- mice was also associated with elevated numbers of P2 peptide-reactive interferon-y (TFN-gamma) secreting cells and alphabeta T cells were present in lymph nodes and spleens. The data suggest that PNS myelin activated T cells from an EAN-resistant mice strain are capable of homing to the PNS. The expanded CD4-8- alphabeta T cells may have helper and effector functions, related to initiation of EAN in the CD4-8- mice. Lack of CD4+ and CD8+ expressing cells does not prevent the initiation of an autoimmune disease.

Animals↗
PubMed1999

Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice.

The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1(+) T cells (NKT cells), and gamma/delta T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1(+) cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3(+) T cell infiltration as well as increased levels of interleukin (IL)-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. Moreover, systemic allergen-specific immunoglobulin (Ig)E and IgG2a levels and the number of IL-4 and interferon gamma-producing splenic cells were diminished in mice depleted of NK1.1(+) cells before the priming regime. Depletion of NK1.1(+) cells during the challenge period only did not influence pulmonary eosinophilic inflammation. CD1d1 mutant mice, deficient in NKT cells but with normal NK cells, developed lung tissue eosinophilia and allergen-specific IgE levels not different from those observed in wild-type mice. Mice deficient in gamma/delta T cells showed a mild attenuation of lung tissue eosinophilia in this model. Taken together, these findings suggest a critical role of NK cells, but not of NKT cells, for the development of allergen-induced airway inflammation, and that this effect of NK cells is exerted during the immunization. If translatable to humans, these data suggest that NK cells may be critically important for deciding whether allergic eosinophilic airway disease will develop. These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.

Allergens↗
PubMed1999

Processing of bacterial antigens for peptide presentation on MHC class I molecules.

Professional antigen-presenting cells (pAPC) can process and present exogenous antigens on major histocompatibility complex class I (MHC-I) molecules. This unusual pathway for antigen presentation may represent a physiologically important step in the course of priming and tolerance induction of CD8+ T cells. In addition, it may play an important role in immunological surveillance for pathogens that survive in vacuolar compartments in APC. The goal of the present review is to discuss recent studies on the processing of bacterial-derived antigens for presentation on MHC-I molecules. The antigen presentation emphasized will include bacteria that remain confined in vacuolar compartments. This is in contrast to antigens derived from bacteria that have intrinsic properties allowing translocation across membranes and access into the classical MHC-I presentation pathway. In particular, presentation of bacterial antigens by dendritic cells (DC) will be emphasized, and MHC-I presentation of antigens derived from apoptotic cells, particularly cells induced to undergo apoptosis by microbial infection, will be presented. Finally, some special aspects of the interaction between bacteria and DC will be discussed as it relates to DC maturation, antigen presentation and T-cell stimulation.

Animals↗
PubMed1999

Selective targeting of habenular, thalamic midline and monoaminergic brainstem neurons by neurotropic influenza A virus in mice.

Infections caused by influenza A virus have been proposed to be associated with neuropsychiatric complications, the mechanisms of which remain to be unravelled. We here report that a neurotropic strain of influenza A virus (A/WSN/33) introduced into the olfactory bulbs of C57BL/6 (B6) mice, selectively attacks habenular, paraventricular thalamic, and brainstem monoaminergic neurons. In the habenular and paraventricular thalamic areas, infection was followed by an almost total loss of neurons within 12 days. In the brain stem monoaminergic areas, viral gene products were eliminated from neurons by 12 days in B6 wildtype mice, but remained for at least 35 days in immunodefective TAP1 (Transporter associated with Antigen Presentation 1) mutant mice. In conclusion, we show that influenza A virus infection in the brain selectively targets regions which have been implicated in neuropsychiatric disturbances, and that this virus can remain for a significant period of time in specific regions of the brain in immunodefective mice.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

MHC class I mosaic mice reveal insights into control of Ly49C inhibitory receptor expression in NK cells.

We have analyzed lymphocyte development in natural MHC class I chimeric mice, generated through a transgenic approach in beta2-microglobulin (beta2m)-/- mice. In these mice, MHC class I+ cells coexist with an equal proportion of MHC class I-deficient cells. These MHC class I mosaic mice had normal numbers of CD8+ T cells, which had a target cell specificity similar to that of wild-type mice. Consequently, the mice did not develop any signs of autoimmunity. They also had normal numbers of NK cells. This allowed an examination of the MHC class I influence on the expression of the Ly49C inhibitory receptor on NK cells. This receptor binds to H-2Kb. It is expressed at low levels on NK cells in wild-type mice of the H-2b haplotype, but at markedly higher levels on NK cells in beta2m-/- mice and other strains of mice lacking expression of H-2Kb. Relatively little is known about how MHC class I molecules affect expression of the Ly49 receptors. Through the analysis of the present MHC class I mosaic mice, we demonstrate that the expression levels of Ly49C on NK cells is a consequence not only of MHC class I expression in the environment, but also of the expression of MHC class I molecules by the NK cells themselves. These findings are discussed in relation to the biological role of the calibration of the Ly49 inhibitory receptor expression in relation to self-MHC class I.

Animals↗
PubMed1998

Rejection of allogeneic and syngeneic but not MHC class I-deficient tumor grafts by MHC class I-deficient mice.

The ability of TAP1-/-, beta2m-/-, and TAP1/beta2m-/- mice to mount rejection responses against allogeneic, syngeneic, and MHC class I-deficient tumor grafts was examined. The results demonstrate a potent ability of TAP1-/- and beta2m-/- as well as TAP1/beta2m-/- mice to reject allogeneic tumors. In contrast to published data, rejection of syngeneic MHC class I-expressing tumors was also observed. This response was specific for the MHC class I-deficient mice, since wild-type mice did not reject syngeneic MHC class I-positive tumors under identical experimental conditions. The rejection response of syngeneic tumors required preimmunization of the mice and was MHC class I specific at the level of priming as well as at the level of the tumor target. Finally, MHC class I-deficient tumor grafts were accepted in MHC class I-deficient mice while similar grafts were rejected in wild-type mice. In summary, while MHC class I-deficient mice have retained a capacity to reject allogeneic tumors. they have gained an ability to reject syngeneic MHC class I-positive tumors and lost the ability to reject MHC class I-negative tumors. The present results are discussed in relation to the role of MHC class I molecules in selecting functional CD8+ T and NK cell repertoires, and the development of cell-mediated immunity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Fine tuning of natural killer cell specificity and maintenance of self tolerance in MHC class I-deficient mice.

TAP1-/-, beta2-microglobulin (beta2m)-/- and TAP1/beta2m-/- mice all express low but quantitatively different levels of MHC class I molecules. Using these mice, we have addressed questions relating to the fine tuning of natural killer (NK) cell specificity and maintenance of self tolerance in the NK cell system. NK cells from B6 wild-type mice killed target cells from TAP1-/-, beta2m-/- and TAP1/beta2m-/- mice in vivo and rejected bone marrow grafts from the same mice in vivo at equivalent levels. NK cells from TAP1-/-, beta2m-/- mice did not kill target cells or reject bone marrow grafts from TAP1/beta2m-/- mice. NK cells in all MHC class I-deficient mice were tolerant to autologous MHC class I-deficient cells, as revealed by in vitro cytotoxicity assays using NK cell effectors activated with the interferon-inducing agent Tilorone, or by in vivo bone marrow graft experiments. However, the self-tolerant state of MHC class I-deficient NK cells was broken by in vitro stimulation with IL-2 for 4 days. Under these conditions, NK cells from the MHC class I-deficient mice killed autologous MHC class I-deficient cells while MHC class I-positive targets were spared. The C-type lectin inhibitory receptor Ly49C has a specificity for H-2Kb and is expressed on a subset of NK1.1+ cells in B6 mice. Wild-type and all MHC class I-deficient mice had similar numbers of Ly49C-positive NK1.1+ cells. However, Ly49C expression was markedly down-regulated on NK1.1+ cells from B6 mice, as compared to TAP1-/-, beta2m-/- and TAP1/beta2m-/- mice. In vitro stimulation of NK cells with IL-2 for 4 days did not significantly change this pattern. The present results are discussed in relation to the role of MHC class I molecules and Ly49 receptors in shaping the NK cell repertoire and raise new questions about maintenance of self tolerance in the NK cell system.

Animals↗
PubMed1998

Differential requirements for CD28 and CD40 ligand in the induction of experimental autoimmune myasthenia gravis.

The interactions of CD28-B7 and CD40-CD40 ligand (CD40L) pathways in T cell costimulation and autoimmune disease are incompletely understood. We sought to address this issue by investigation of the genesis of acetylcholine receptor (AChR)-induced antibody-mediated experimental autoimmune myasthenia gravis (EAMG) in CD28- and CD40L-deficient mice (CD28-/-, CD40L-/-). Compared to wild-type mice, the CD28-/- mice became less susceptible, and CD40L-/- mice were completely resistant to EAMG induction. Analysis of T helper functions, reflected by cytokine responses, revealed a switch to a Th1 profile in CD28-/- mice. Consistently, levels of serum AChR-specific antibodies of the IgG1 isotype were decreased in CD28-/- mice. In the CD40L-/- mice, both Th1 and Th2 cytokine responses were diminished, and T cell-dependent AChR-reactive B cell responses were more severely impaired than in the CD28-/- mice. Thus, CD28 and CD40L are differentially required for induction of EAMG.

Amino Acid Sequence↗
PubMed1998

The Qa-1b molecule binds to a large subpopulation of murine NK cells.

Recent studies on human NK cells have demonstrated that the NK cell CD94/NKG2 receptors bind to the nonclassical MHC class I molecule HLA-E. A functional CD94/NKG2 complex has not yet been identified in rodents, but cDNA encoding rat and mouse CD94 and NKG2 have recently been cloned, suggesting that CD94/NKG2 receptors may exist in species other than man. The mouse nonclassical MHC class I molecule Qa-1 shares several features with HLA-E. This suggests that Qa-1 may be similarly recognized by murine NK cells. To study the ability of Qa-1 to bind to murine NK cells, we have produced a soluble tetrameric form of Qa-1b. In the present study, we demonstrate that Qa-1b tetramers distinctly bind to a large subset of fresh or IL-2-activated NK1.1+/CD3- splenocytes independently of the expression of Ly49 inhibitory receptors. Binding occurs whether NK cells have evolved in an MHC class I-expressing or in an MHC class I-deficient environment. Our data suggest the existence of a Qa-1-recognizing structure on a large subpopulation of murine NK cells that may be similar to the human CD94/NKG2 heterodimeric complex.

Animals↗
PubMed1997

TAP peptide transporter-independent presentation of heat-killed Sendai virus antigen on MHC class I molecules by splenic antigen-presenting cells.

Immunization of C57BL/6 (B6) mice with heat-killed Sendai virus generates a Sendai virus-specific CD8+ T cell response. This suggests that APC have the capacity to take up and present exogenous (nonreplicative) Sendai virus Ag on MHC class I molecules. Little is known about the intracellular requirements for processing of this form of Ag and its presentation on MHC class I. Therefore, we have studied the processing and presentation of heat-killed Sendai virus Ag on MHC class I molecules in splenic APC. Heat-killed Sendai virus Ags were efficiently processed by normal B6 as well as by TAP-1(-/-) splenic APC. Presentation was MHC class I restricted, since no presentation was seen by APC from TAP-1/beta2m-/- mice that lack expression of MHC class I. Presentation occurred even in the presence of brefeldin A, but was blocked by cytochalasin D as well as chloroquine. Finally, B6 as well as TAP-1(-/-) splenic APC, loaded with heat-killed Sendai virus Ag in vitro, primed naive CD8+ T cells in vivo. These studies suggest the existence of a TAP-independent pathway for Ag presentation on MHC class I in normal splenic APC, bearing many similarities with the MHC class II pathway for Ag presentation. The present results are discussed in relation to the events underlying the processing and presentation of exogenous Ag on MHC class I, the molecular basis for CD8+ T cell priming during viral infections, and prospects for vaccine development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Generation of CD8+ T cells specific for transporter associated with antigen processing deficient cells.

Cells with impaired transporter associated with antigen processing (TAP) function express low levels of cell surface major histocompatibility complex (MHC) class I molecules, and are generally resistant to lysis by MHC class I restricted cytotoxic T lymphocytes (CTLs). Here we report the generation of MHC class I restricted CD8(+) CTLs that surprisingly require target cell TAP deficiency for efficient recognition. C57BL/6 (B6) mice immunized with syngenic B7-1 (CD80) expressing TAP-deficient cells generated a potent CTL response against both TAP-deficient RMA-S tumor cells and TAP-deficient Con A blasts, whereas the corresponding TAP-expressing target cells were considerably less susceptible or resistant to lysis. The CTL epitopes recognized were expressed also by the human TAP-deficient cell line T2, transfected with appropriate MHC class I molecules. B6 mice immunized with B7-1-transfected TAP-deficient RMA-S cells were protected from outgrowth of a subsequent RMA-S tumor challenge. These findings are discussed in relation to the biochemical nature of MHC class I dependent CTL epitopes associated with impaired TAP function, as well as implications for immunotherapy and autoimmunity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

NK cell receptor calibration: effects of MHC class I induction on killing by Ly49Ahigh and Ly49Alow NK cells.

NK cells from C57BL/6 (B6) mice and H-2Dd transgenic B6 (D8) mice express different levels of the inhibitory receptor Ly49A, and they also differ in their target cell specificity. Here, we examined this differential specificity with respect to the role of the Ly49A receptor expression on effector cells and levels of H-2Dd inhibitory ligands on target cells. NK cells from D8 mice express low levels of Ly49A receptor (Ly49Alow), and are able to kill SP2/0 tumor cells in spite of their expression of H-2Dd. H-2Dd is expressed at reduced levels on SP2/0 cells; when these were increased three- to fivefold after IFN-gamma treatment, the killing by Ly49Alow NK cells from D8 mice was markedly reduced. Efficient killing was restored when the effectors were preincubated with anti-Ly49A F(ab')2 Abs. A separate experimental system was based on D8 TAP1-deficient Con A blasts exogenously loaded with H-2Dd-specific peptides. In this system, higher levels of cell surface H-2Dd had to be induced by peptide to inhibit D8 Ly49Alow NK cells to an extent similar to that of B6 Ly49Ahigh NK cells. Ly49A receptors on NK cells from H-2Dd transgenic mice are thus functional, although they require high levels of ligand to inhibit progression of the NK-target cell interaction. The data are in favor of the "receptor-calibration" model, which suggests that down-regulation of inhibitory receptors on NK cells may be useful in order for NK cells to discriminate between normal and reduced levels of MHC class I molecules.

Animals↗
PubMed1997

Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10.

The MHC class I molecules present antigenic peptides to CTL. The peptides are delivered to the secretory pathway by TAP, which is formed by the association of MHC-encoded TAP1 and TAP2 gene products. Tumor cells incubated or transfected with IL-10 had decreased but peptide-inducible expression of MHC class I, decreased sensitivity to MHC class I-restricted CTL, and increased NK sensitivity. We here demonstrate that IL-10 expression in the murine lymphoma RMA inhibits the TAP-dependent translocation of peptides to the endoplasmic reticulum, resulting in accumulation of immature MHC class I molecules in the endoplasmic reticulum and subsequently low expression of cell surface MHC class I molecules. This finding is explained by a down-regulation of expression of TAP1 and TAP2, observed in IL-10-transfected RMA cells as well as in IL-10-transfected P815 mastocytoma cells. In the J558L plasmacytoma cell line, constitutively expressing high levels of IL-10, increased TAP-dependent translocation of peptides and expression of cell surface MHC class I could be induced by IL-10 antisense expression. IL-10 is the first example to demonstrate that a cytokine can decrease the expression and function of the TAP1/2 molecular complex and, in more general terms, the first example of a cytokine with an inhibitory effect on MHC class I-mediated Ag presentation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Altered expression of Ly49 inhibitory receptors on natural killer cells from MHC class I-deficient mice.

MHC class I molecules in the host affect the specificity of NK cells. Previous work has suggested that this specificity is conferred by the expression of products encoded by the Ly49 gene family. This gene family encodes receptors that upon specific recognition of MHC class I ligands mediate an inhibitory signal that prevents killing by NK cells. The pattern of expression of the Ly49 MHC class I binding inhibitory receptors on NK cells is thought to be adapted to the host to ensure the generation of a self-tolerant, yet functional, NK cell repertoire. In the present study we have examined the expression of inhibitory receptors (Ly49A, Ly49C, and Ly49G2) on NK1.1+ cells from B6 (H-2b) and D8 (B6 mice transgenic for H-2Dd) mice as well as corresponding TAP1 -/-, beta2m -/-, and TAP1/beta2m -/- mutants of these mice. We demonstrate that receptor expression on NK1.1+ cells can be specifically modulated by host MHC class I molecules in at least two different ways: alteration of numbers of cells expressing a given receptor and modulation of the levels of expression of a given receptor at the cell surface. The degree of this modulation varies significantly among the various receptors studied and may depend upon the nature of their MHC class I ligands. The results are discussed in relation to the influence of MHC class I molecules on the development of an NK cell repertoire.

Animals↗
PubMed1997

Major histocompatibility complex class I-independent killing of xenogeneic targets by rat allospecific natural killer cells.

Major histocompatibility complex class I molecules can inhibit mouse as well as human natural killer (NK) cell cytotoxicity. In contrast, antigens encoded in the RT1.C region of the rat MHC gene complex have been suggested to trigger, rather than inhibit, rat NK cells. In an attempt to analyze rat NK cell specificity, with respect to the cross-species difference that may exist in NK cell-mediated cytotoxicity, we investigated the ability of interleukin 2-activated, allospecific rat NK cells to recognize MHC class I-positive and -deficient target cells of mouse and human origins. Recognition of xenogeneic target cells by rat allospecific NK cells was found to be MHC class I independent; target cell MHC class I was not required for killing, and expression of different sets of mouse and human MHC class I molecules did not influence the cytotoxic response. These results indicate that rat NK cells can recognize xenogeneic nontransformed cells by mechanisms not related to target cell MHC class I expression, and that mouse and human MHC class I molecules, at least among those tested in this study, are unable to confer inhibition of rat NK cells.

Animals↗
PubMed1997

Spread of measles virus through axonal pathways into limbic structures in the brain of TAP1 -/- mice.

The spread of measles virus into the brain was studied exploiting the olfactory pathway, which represents an important route of neuroinvasion by viruses. The virus was injected into the main olfactory bulb of wild-type mice and mice with disrupted TAP1 gene (TAP refers to the Transporter associated with Antigen Presentation), which codes for products essential for the cell-mediated immune response. Virus invasion was monitored for 4 weeks by immunohistochemistry. The distribution of measles virus was found to be restricted to brain areas connected with the olfactory bulbs. However, in the wild-type mice there was a marked infiltration of lymphocytes in the infected brain structures, and the virus did not pass beyond the piriform cortex. In the TAP1 -/- mice the virus spread more extensively along olfactory projections into the limbic system and monoaminergic brainstem neurons. Infected mice of both types developed seizures, which may have been focally evoked from the piriform cortex. This study provides evidence that measles virus can spread through axonal pathways in the brain. The findings obtained in the gene-manipulated mice point out that a compromised immune state of the host may potentiate targeting of virus to the limbic system through olfactory projections.

ATP Binding Cassette Transporter, Subfamily B, Mem↗