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PubMed2004

Antigen presentation by a macrophage-like cell line persistently infected with respiratory syncytial virus.

Severe infection by the human respiratory syncytial virus (RSV) early in life is associated with subsequent recurrent airway disease presumably mediated by dysregulation of the local immune response. Dysfunction of the immune response may be related to impaired macrophage functions. We have previously reported that RSV persistence in a macrophage culture (MPhiper) alters Fcgamma receptors (FcgammaR)-mediated phagocytosis and the production of pro-inflammatory cytokines. Here, we determined whether the ability of macrophages to process and present antigens and to stimulate RSV-specific CD8(+) T cells was altered in MPhiper. We also examined the level of expression of MHC class I molecules in MPhiper and the ability of these cells to present viral antigens to specific T lymphocytes. Our results showed that antigen processing and presentation were not altered by chronic RSV infection, and suggested that MPhiper were able to stimulate RSV-specific CD8(+) T lymphocytes.

Animals↗

PubMed1997

Inhibitory effects of thymus-independent type 2 antigens on MHC class II-restricted antigen presentation: comparative analysis of carbohydrate structures and the antigen presenting cell.

The role of thymus-independent type 2 (TI-2) antigens (polysaccharides) on the MHC-II-restricted processing of protein antigens was studied in vitro. In general, antigen presentation is inhibited when both peritoneal and splenic macrophages (M phi) as well as Küpffer cells (KC) are preincubated with acidic polysaccharides or branched dextrans. However, the inhibitory effect of neutral polysaccharides was minimal when KC were used as antigen presenting cells (APC). Morphological evaluation of the uptake of fluoresceinated polysaccharides clearly correlates with this selective and differential interference. Polysaccharides do not block MHC-I-restricted antigen presentation. Some chemical characteristics shared by different saccharides seem to be specially related to their potential inhibitory abilities: (i) those where two anomeric carbon atoms of two interlinked sugars and (ii) those containing several sulfate groups per disaccharide repeating unit. No polysaccharide being inhibitory in M phi abrogated antigen processing in other APC: lipopolysaccharide-activated B cells, B lymphoma cells, or dendritic cells (DC). Using radiolabeled polysaccharides it was observed that DC and B cells incorporated less radioactivity as a function of time than M phi. Morphological evaluation of these different APC incubated for extended periods of time with inhibitory concentrations of polysaccharides revealed intense cytoplasmic vacuolization in M phi but not in B cells or DC. The large majority of M phi lysosomes containing polysaccharides fail to fuse with incoming endocytic vesicles and delivery of fluid-phase tracers was reduced, suggesting that indigestible carbohydrates reduced the fusion of these loaded lysosomes with endosomes containing recently internalized tracers. It is suggested that the main causes of this antigen presentation blockade are (i) the chemical characteristics of certain carbohydrates and whether the specific enzymatic machinery for their intracellular degradation exists; and (ii) the different phagocytic abilities of distinct APC populations, fluid-phase pinocytosis and receptor-mediated saccharide uptake, and existence of a differential antigen-processing pathway in M phi and DC or B cells, which could be based on a polysaccharide-inhibited step present in M phi but unaffected or irrelevant in both B cells and DC.

Animals↗

PubMed1988

T cells can present antigens such as HIV gp120 targeted to their own surface molecules.

To trigger class II-restricted T cells, antigen presenting cells have to capture antigens, process them and display their fragments in association with class II molecules. In most species, activated T cells express class II molecules; however, no evidence has been found that these cells can present soluble antigens. This failure may be due to the inefficient capture, processing or display of antigens in a stimulatory form by T-cells. The capture of a soluble antigen, which is achieved by nonspecific mechanisms in macrophages and dendritic cells, can be up to 10(3) times more efficient in the presence of surface receptors, such as surface immunoglobulin on B cells that specifically bind antigen with high affinity. We asked whether T cells would be able to present soluble antigens that bind to their own surface molecules. Here we show that such antigens can be effectively processed and presented by both CD4+- and CD8+-bearing human T cells. This indicates that T cells are fully capable of processing and displaying antigens and are mainly limited in antigen presentation by their inefficiency at antigen capture.

Antibodies, Monoclonal↗

PubMed1981

Major histocompatibility complex-restricted antigen presentation to antigen-reactive T cells by B lymphocyte tumor cells.

Previous reports have demonstrated that accessory cells function to present soluble protein antigens in association with gene products encoded within the I region of the major histocompatibility complex (MHC) to antigen-reactive T helper cells. The biochemical events that occur during antigen presentation are, however, not well-documented primarily because of the difficulties involved in purifying sufficient numbers of homogeneous antigen-presenting cells. In this paper, a number of Ia-positive B lymphocyte tumor lines are shown to be capable of presenting soluble protein antigens to antigen-reactive continuous T cell lines in an MHC-restricted fashion. The characterization of the antigen presentation function of these tumor cells indicates that the tumor cells have many of the functional antigen-presenting characteristics previously thought to be limited to macrophages. These tumor cells should provide a useful model system for determining the biochemical events that occur in antigen uptake and processing as well as for determining the potential interactions between processed antigen and Ia molecules on the plasma membrane of these antigen-presenting cells.

Animals↗

PubMed1987

Presentation of soluble antigen to human T cells by products of multiple HLA-linked loci: analysis of antigen presentation by a panel of cloned, autologous, HLA-mutant Epstein-Barr virus-transformed lymphoblastoid cell lines.

Epstein-Barr virus-transformed human B lymphoblastoid cell lines (EBV-LCL) can present soluble antigens to antigen-primed T lymphocytes. In this study, we used HLA antigen-loss mutants of an EBV-LCL line (LCL 721) to demonstrate that the presentation of a soluble antigen from Candida albicans (CAN) by EBV-LCL to primed T cells can be restricted by multiple HLA determinants. Haplotype-deletion mutants that contained only the maternal or only the paternal HLA-haplotype were used to demonstrate the preferential role of autologous HLA antigens in presenting soluble antigens to Candida-primed T cells from the donor of LCL-721, and to T cells from her mother and father. Immunoselected mutants of LCL-721 showing a variety of distinct phenotypes that are deficient in HLA-DR, DQ, or DP antigen expression were tested as antigen-presenting cells. The antigen-presenting ability of these class II deficient EBV-LCL variants weakened with progressive loss of class II HLA determinants expressed on the cell surface. Our study, therefore, provides evidence for multiple HLA restriction determinants, including HLA-DR, DQ, and DP. Furthermore, LCL lacking all HLA-DR, DQ, and DP expression because of homozygous deletion of these MHC class II genes still presented CAN and Tetanus toxid (TET), although to a much lesser degree than presented by LCL-721. This suggests that determinants other than DR, DQ, and DP which are expressed on these EBV-LCL may also function as restriction elements for the proliferative T-cell response to soluble antigens.

Antigen-Presenting Cells↗

PubMed1983

Local and systemic immune responses to intestinally presented antigen.

We have investigated the ability of the gut-associated lymphoid tissues (GALT) to react against standard antigens presented via different routes of administration. When antigens were presented directly to GALT, either by an injection into the Peyer's patches or via a mechanically damaged lamina propria, a rapid and vigorous immune response ensued. This was manifested systemically as an antigen-specific humoral antibody response in the serum and locally as an antigen-specific immunoglobulin A response in the bile. These results indicate that GALT is capable of reacting to foreign materials penetrating the gut wall. Additional experiments demonstrated that the extended feeding of degraded iota carrageenan, a material known to produce non-specific mucosal inflammation, caused GALT to react to antigenic molecules present within the gastro-intestinal tract and enhanced both serum and biliary antibody responses against specific gut commensal microorganisms. The immunological significance of these observations is discussed.

Administration, Oral↗

PubMed2004

The ABCs of artificial antigen presentation.

Artificial antigen presentation aims to accelerate the establishment of therapeutic cellular immunity. Artificial antigen-presenting cells (AAPCs) and their cell-free substitutes are designed to stimulate the expansion and acquisition of optimal therapeutic features of T cells before therapeutic infusion, without the need for autologous antigen-presenting cells. Compelling recent advances include fibroblast AAPCs that process antigens, magnetic beads that are antigen specific, novel T-cell costimulatory combinations, the augmentation of therapeutic potency of adoptively transferred T lymphocytes by interleukin-15, and the safe use of dendritic cell-derived exosomes pulsed with tumor antigen. Whereas the safety and potency of the various systems warrant further preclinical and clinical studies, these emerging technologies are poised to have a major impact on adoptive T-cell therapy and the investigation of T cell-mediated immunity.

Animals↗

PubMed1988

B-T lymphocyte interactions in experimental autoimmune myasthenia gravis: antigen presentation by rat/mouse hybridoma lines secreting monoclonal antibodies against the nicotinic acetylcholine receptor.

Many, but not all rat/mouse B hybridoma cells, producing monoclonal antibodies against determinants on the nicotinic acetylcholine receptor (AChR) of the electric organ of Torpedo californica, were able to immunologically present antigen to AChR-specific, Ia-compatible CD4+ T lymphocyte lines. Most of the hybridomas presented AChR in a privileged manner, i.e. they present AChR even more effectively than macrophages or dendritic cells. However, in the presentation of antigens other than AChR, they were inferior to macrophages. Moreover, some hybridomas were able to present AChR not only in soluble state, but also in membrane vesicles. Privileged presentation of AChR by hybridomas depended on the reactivity of the secreted immunoglobulins with epitopes of the AChR alpha chain, and on the expression of major histocompatibility complex class II antigens on the hybridoma cell surface. There was, however, no quantitative correlation between the actual AChR presentation capacity of one clone and the density of its surface Ia. Neither fine specificity nor isotype of hybridoma immunoglobulin are critical in determining privileged AChR presentation. We postulate that different hybridomas vary in their ability to take up soluble and particulate antigen, to process and to re-express them on the cellular membrane. This capacity may determine their efficiency to present antigen to T cells.

Animals↗

PubMed2000

Antigen-presenting cells in the female reproductive tract: influence of estradiol on antigen presentation by vaginal cells.

The objective of the present study was to define the afferent arm of the mucosal immune system in the lower female reproductive tract. We report here that antigen presentation by vaginal cells is under hormonal control. When vaginal cells from ovariectomized rats treated with estradiol (0.01-10 microg) were incubated with ovalbumin-specific T cells and ovalbumin, a dose-dependent inhibition of antigen presentation was measured. In time course studies, estradiol given to ovariectomized rats inhibited vaginal cell antigen presentation within 24 h after a single injection, relative to that seen in saline controls. To determine whether changes in antigen presentation were attributable to the effect of estradiol on the number of antigen-presenting cells (APCs) in the vagina, tissues were analyzed by immunohistochemistry. Our findings indicate that estradiol inhibited antigen presentation without affecting the number of major histocompatibility complex class II positive cells and at a time when macrophage/dendritic cells/granulocytes in the vagina increase in response to estradiol treatment. Antibody neutralization studies indicated that antigen presentation by vaginal cells from ovariectomized rats is mediated through class II and involves the expression of transmembrane proteins B7.1 and B7.2. In other studies, vaginal APCs interact with thymus APCs to synergistically enhance antigen presentation under conditions in which vaginal antigen presentation is inhibited by estradiol. Analysis of conditioned media indicates that enhancement of thymus antigen presentation involves the release of a soluble factor(s) into the culture media of vaginal cells. When spleen cells were cocultured with vaginal cells from saline-treated rats, proliferation increased in the presence of concanavalin A and/or phytohemagglutinin and decreased with lipopolysaccharide, relative to spleen cells and mitogen alone. In contrast, when incubated with vaginal cells from estradiol-treated rats, spleen cell proliferation was not affected with concanavalin but was inhibited with phytohemagglutinin and lipopolysaccharide. These studies demonstrate that estradiol regulates antigen presentation by vaginal cells and that vaginal cells, in turn, influence antigen presentation, as well as B and T cell proliferation.

Animals↗

PubMed1993

Inhibition by chloroquine of the class II major histocompatibility complex-restricted presentation of endogenous antigens varies according to the cellular origin of the antigen-presenting cells, the nature of the T-cell epitope, and the responding T cell.

Chloroquine treatment of antigen-presenting cells (APC) was explored as a tool to investigate the processing pathway for major histocompatibility complex (MHC) class II-restricted presentation of the endogenous secreted hen egg lysozyme (HEL) and transmembrane measles virus haemagglutinin (HA). A 72-hr pretreatment of the APC with 25 microM chloroquine blocked the presentation of the HEL(52-61) T-cell epitope generated from endogenous HEL to the I-Ak-restricted 3A9 T-cell hybridoma by MHC class II-transfected L cells expressing the invariant chain (Ii). The presentation of exogenously added HEL peptides was not affected. Under the same conditions, no inhibition of the presentation of HEL(106-116) to the I-Ed-restricted G28 high-avidity T-cell hybridoma, nor of HA when synthesized by L cells, was observed. When B-lymphoid APC were used, inhibition was observed in every case with a low number of B APC pretreated for 48 hr with chloroquine prior to the T-cell stimulation test. Moreover, addition of chloroquine to untreated B APC during the T-cell stimulation assay was sufficient to inhibit completely the presentation of HEL(106-116) to the B10.D24.42 low avidity T-cell hybridoma. Altogether these studies suggest that an apparent resistance of endogenous Ag presentation to chloroquine inhibition may not necessarily indicate the existence of a non-endosomal pathway but may be due to the nature of the T-cell epitope, to the use of 'non-professional' APC such as L cells, to the use of T cells of high avidity, and to high amounts of pre-existing MHC class II-peptide complexes expressed by the APC. We demonstrate here that, at least in conventional APC such as B cells, class II-restricted presentation of both endogenous secreted HEL and transmembrane HA involves an endosomal pathway.

Animals↗

PubMed1989

Antigen presentation by non-immune B-cell hybridoma clones: presentation of synthetic antigenic sites reveals clones that exhibit no specificity and clones that present only one epitope.

Recently, we reported the preparation and antigen-presenting properties of hybridoma B-cell clones obtained after fusing non-secreting, non-antigen presenting Balb/c 653-myeloma cells with non-immune SJL spleen cells. It was found that antigen presentation at the clonal level can be specific or non-specific, depending on the particular B-cell clone. In the present work, one specific and one general presenter B-cell clones were tested for their epitope presentation ability to SJL T-cells that were specific to lysozyme or myoglobin. B-cell clone A1G12, a general presenter which presented both lysozyme and myoglobin to their respective T-cell lines, was found to present all five myoglobin epitopes while clone A1L16, a lysozyme specific presenter presented only one of the three epitopes of lysozyme. The latter reveals a hitherto unknown submolecular specificity (to a given epitope within a protein) for antigen presenting cells at the clonal level. Therefore, the specificity of T-cell recognition does not only derive from the T-cell but may also be dependent on the epitope specificity of the antigen-presenting B-cell.

Amino Acid Sequence↗

PubMed2005

Tails of wonder: endocytic-sorting motifs key for exogenous antigen presentation.

Antigen-presenting molecules, including MHC I, II and CD1, have central roles in the induction of T cell-mediated immunity against pathogens and tumors and also in the maintenance of tolerance towards self-antigens. The presentation of exogenously derived peptide and lipid antigens to specific T cells by professional antigen-presenting cells (pAPCs) is an essential part of both processes. Exogenous antigen loading takes place mostly within specialized endocytic and phagocytic compartments of pAPCs and targeting of antigen-presenting molecules to these intracellular compartments is mediated by highly conserved cytoplasmic sorting motifs. Recent data have revealed that the cytoplasmic tails of antigen-presenting molecules, by controlling the access of these molecules to exogenously derived antigens, have a crucially important and largely underappreciated role in the generation of tolerance and T-cell mediated immunity.

Amino Acid Motifs↗

PubMed1985

Antigen presentation by EBV-B cells to resting and activated T cells: role of interleukin 1.

We have previously demonstrated that Epstein Barr virus-transformed human B lymphocytes (EBV-B cells) present antigen to activated T cells (lines and clones) in a MHC-restricted manner. In the present study, using EBV-nonimmune donors, we demonstrate that EBV-B cells are unable to trigger tetanus toxoid (TT) antigen-specific proliferation in autologous highly purified resting T cells. EBV-B cells from these same individuals were able to present TT to autologous TT-specific activated T cell blasts (Tbl). The inability of EBV-B cells to present TT to resting T cells was not caused by defective antigen processing by EBV-B cells. Thus, paraformaldehyde treatment of antigen-pulsed EBV-B cells did not impair their ability to trigger proliferation of antigen-specific Tbl, and EBV-B cells pulsed with antigen in the presence of autologous TT-specific T cell blasts did not present antigen to resting T cells. Furthermore, antigen-specific proliferation of resting T cells triggered by monocytes was enhanced rather than suppressed by EBV-B cells. The addition of partially purified human IL 1 allowed EBV-B cells to present TT antigen to resting T cells, suggesting that failure to secrete IL 1 contributed to the failure of EBV-B cells to present antigen. IL 1 could not be detected in supernatants of EBV-B cells stimulated with Staphylococcus epidermidis, concanavalin A, and TT antigen in the presence or absence of up to 5% autologous T cells. The differential capacity of EBV-B cells to present antigen to resting T cells vs activated T cells correlated with the T cell requirement for IL 1, because a rabbit antibody to human IL 1 inhibited the monocyte-supported proliferation of resting T cells but not that of activated T cells. These results suggest that the inability of EBV-B cells to present antigen to resting T cells is related to their inability to secrete detectable IL 1.

Adult↗

PubMed1996

Interleukin 3 enhances cytotoxic T lymphocyte development and class I major histocompatibility complex "re-presentation" of exogenous antigen by tumor-infiltrating antigen-presenting cells.

We show that interleukin 3 (IL-3) enhances the generation of tumor-specific cytotoxic T lymphocytes (CTLs) through the stimulation of host antigen-presenting cells (APCs). The BALB/c (H-2d) spontaneous lung carcinoma line 1 was modified by gene transfection to express ovalbumin as a nominal "tumor antigen" and to secrete IL-3, a cytokine enhancing myeloid development. IL-3-transfected tumor cells are less tumorigenic than the parental cell line, and tumor-infiltrating lymphocytes isolated from these tumors contain increased numbers of tumor-specific CTLs. By using B3Z86/90.14 (B3Z), a unique T-cell hybridoma system restricted to ovalbumin/H-2b and implanting the tumors in (BALB/c x C57BL/6)F1 (H-2d/b) mice, we demonstrate that the IL-3-transfected tumors contain an increased number of a rare population of host cells that can process and "re-present" tumor antigen to CTLs. Electron microscopy allowed direct visualization of these host APCs, and these studies, along with surface marker phenotyping, indicate that these APCs are macrophage-like. The identification of these cells and their enhancement by IL-3 offers a new opportunity for tumor immunotherapy.

Animals↗

PubMed1994

The bio-logical role of invariant chain (Ii) in MHC class II antigen presentation.

Foreign antigens are internalized by antigen presenting cells by endocytosis and processed to peptides. To enable presentation of antigenic peptides by MHC class II molecules, these molecules have to be sorted to endosomal compartments where they can meet and bind the peptides. Invariant chain is complexed with MHC class II molecules and contains sorting signals responsible for MHC class II accumulation in endosomes. Invariant chain also has several other features contributing to the immune system's specific combat against invaders.

Animals↗

PubMed1996

Heat shock increases antigenic peptide generation but decreases antigen presentation.

The heat shock response is a universal and highly conserved cellular response to stress. We describe here the effect of elevated temperature on the capacity of B cells to present antigen. Heat shock markedly affects the ability of these cells to process and present tetanus toxin to class II-restricted T cell clones. Inhibition of antigen presentation is due neither to a modification of antigen capture nor to a variation of major histocompatibility complex (MHC) class II molecule synthesis and cell surface expression. Stressed and nonstressed B cells are able to present peptides loaded at the cell surface with the same efficiency. Nevertheless, heat shock leads to an increase of antigen peptide generation in subcellular compartments; an enhancement of cathepsin B activity is also observed. These data suggest that such a stress induces a failure in the intracellular peptide loading onto MHC class II molecules.

Amino Acid Sequence↗

PubMed2004

Endothelial cells present antigens in vivo.

BACKGROUND: Immune recognition of vascular endothelial cells (EC) has been implicated in allograft rejection, protection against pathogens, and lymphocyte recruitment. However, EC pervade nearly all tissues and predominate in none, complicating any direct test of immune recognition. Here, we examined antigen presentation by EC in vivo by testing immune responses against E. coli beta-galactosidase (beta-gal) in two lines of transgenic mice that express beta-gal exclusively in their EC. TIE2-lacZ mice express beta-gal in all EC and VWF-lacZ mice express beta-gal in heart and brain microvascular EC. RESULTS: Transgenic and congenic wild type FVB mice immunized with beta-gal expression vector DNA or beta-gal protein generated high titer, high affinity antisera containing comparable levels of antigen-specific IgG1 and IgG2a isotypes, suggesting equivalent activation of T helper cell subsets. The immunized transgenic mice remained healthy, their EC continued to express beta-gal, and their blood vessels showed no histological abnormalities. In response to beta-gal in vitro, CD4+ and CD8+ T cells from immunized transgenic and FVB mice proliferated, expressed CD25, and secreted IFN-gamma. Infection with recombinant vaccinia virus encoding beta-gal raised equivalent responses in transgenic and FVB mice. Hearts transplanted from transgenic mice into FVB mice continued to beat and the graft EC continued to express beta-gal. These results suggested immunological ignorance of the transgene encoded EC protein. However, skin transplanted from TIE2-lacZ onto FVB mice lost beta-gal+ EC and the hosts developed beta-gal-specific antisera, demonstrating activation of host immune effector mechanisms. In contrast, skin grafted from TIE2-lacZ onto VWF-lacZ mice retained beta-gal+ EC and no antisera developed, suggesting a tolerant host immune system. CONCLUSION: Resting, beta-gal+ EC in transgenic mice tolerize specific lymphocytes that would otherwise respond against beta-gal expressed by EC within transplanted skin. We conclude that EC effectively present intracellular "self" proteins to the immune system. However, antigen presentation by EC does not delete or anergize a large population of specific lymphocytes that respond to the same protein following conventional immunization with protein or expression vector DNA. These results clearly demonstrate striking context sensitivity in the immune recognition of EC, a subtlety that must be better understood in order to treat immune diseases and complications involving the vasculature.

Animals↗

PubMed1991

Human bronchial epithelial cells modulate CD3 and mitogen-induced DNA synthesis in T cells but function poorly as antigen-presenting cells compared to pulmonary macrophages.

This study was undertaken to investigate the ability of bronchial epithelial cells (ECs) to function as accessory cells. Pulmonary monocytes were our reference cells. ECs and pulmonary monocytes were isolated from the bronchial mucosa and pulmonary parenchyma of subjects undergoing lobectomy for standard clinical reasons. Circulating autologous T cells were rigorously depleted of accessory cells to the extent that they lost the capacity to respond to mitogenic lectins alone. ECs restored mitogen-induced DNA synthesis and DNA synthesis triggered by CD3 cross-linking in T cells, as did pulmonary macrophages, and this was unrelated to HLA-DR expression. The ability of promoting T cell proliferation after CD3 cross-linking was, in part, due to the secretory products of ECs, since their supernatants were also effective. Interferon-gamma-treated ECs were capable of presenting antigens to autologous T cells. This was an HLA-DR-restricted phenomenon, but EC efficiency in this system was less than 40% of efficiency demonstrated by pulmonary monocytes. However, ECs greatly upregulated antigen-specific responses supported by pulmonary monocytes.

Antigen-Presenting Cells↗