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Results for “antigen presentation”

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PubMed1992

Tumor antigen presentation by epidermal antigen-presenting cells in the mouse: modulation by granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and ultraviolet radiation.

I-A+ epidermal antigen-presenting cells (APCs, Langerhans cells) have been shown to present tumor-associated antigens (TAAs) and to induce tumor immunity in vivo. This study examined the effects of ultraviolet radiation (UVR) and the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha) on the ability of epidermal cells (ECs) to induce or to elicit immunity against the murine spindle cell tumor S1509a. Naive syngeneic mice were immunized three times at weekly intervals with ECs that had been cultured in GM-CSF for 18 h and then pulsed with TAA derived from S1509a. This resulted in protective immunity against subsequent tumor challenge, providing a model to study the conditions required for sensitization against TAAs by epidermal APCs. Culture of ECs in GM-CSF was required for induction of significant protective tumor immunity, and UV irradiation or incubation in TNF-alpha for 2 h after GM-CSF incubation abrogated the immunostimulatory effect of GM-CSF. However, unlike UVR, TNF-alpha did not significantly inhibit the induction of immunity when ECs were exposed to TNF-alpha before overnight incubation in GM-CSF, together with GM-CSF, or after pulsing with TAA, and anti-TNF-alpha antibody treatment did not abrogate the effects of UVR on this system. Furthermore, TNF-alpha incubation of ECs augmented their ability to elicit delayed-type hypersensitivity (DTH) and also enhanced elicitation of DTH by GM-CSF-cultured ECs, whereas UV-irradiation reduced it in a dose-dependent fashion. Taken together, these results demonstrate that GM-CSF, TNF-alpha, and UVR are significant regulators of tumor antigen presentation by epidermal APCs and that the effects of the cytokines examined differ with regard to induction or elicitation of immunity.

Animals↗

PubMed2000

Sequential cleavage by metallopeptidases and proteasomes is involved in processing HIV-1 ENV epitope for endogenous MHC class I antigen presentation.

Antigenic peptides derived from viral proteins by multiple proteolytic cleavages are bound by MHC class I molecules and recognized by CTL. Processing predominantly takes place in the cytosol of infected cells by the action of proteasomes. To identify other proteases involved in the endogenous generation of viral epitopes, specifically those derived from proteins routed to the secretory pathway, we investigated presentation of the HIV-1 ENV 10-mer epitope 318RGPGRAFVTI327 (p18) to specific CTL in the presence of diverse protease inhibitors. Both metalloproteinase and proteasome inhibitors decreased CTL recognition of the p18 epitope expressed from either native gp160 or from a chimera based on the hepatitis B virus secretory core protein as carrier protein. Processing of this epitope from both native ENV and the hepatitis B virus secretory core chimeric protein appeared to proceed by a TAP-dependent pathway that involved sequential cleavage by proteasomes and metallo-endopeptidases; however, other protease activities could replace the function of the lactacystin-sensitive proteasomes. By contrast, in a second TAP-independent pathway we detected no contribution of metallopeptidases for processing the ENV epitope from the chimeric protein. These results show that, in the classical TAP-dependent MHC class I pathway, endogenous Ag processing of viral proteins to yield the p18 10-mer epitope requires metallo-endopeptidases in addition to proteasomes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Bronchoalveolar lavage cells from sarcoidosis patients and healthy controls can efficiently present antigens.

OBJECTIVES: The interaction between antigen-presenting cells (APC) and T lymphocytes, that recognize the antigen-HLA complex using its T cell-receptor for antigen, is of crucial importance for a subsequent specific immune response. In patients with pulmonary sarcoidosis, the local antigen-presenting capacity in the lungs has been suggested to be abnormally enhanced, and implicated in the immunopathogenesis of the disease. This study was aimed at increasing the understanding of the capacity to present antigens by APC in the lung compartment. DESIGN AND SUBJECTS: We used bronchoalveolar lavage (BAL) cells and paired peripheral blood mononuclear cells (PBMC) of six sarcoidosis patients and two healthy controls to stimulate in total eight well characterized T-cell clones with known HLA and antigen specificities. All subjects were HLA typed. RESULTS: BAL cells of sarcoidosis patients as well as of healthy controls efficiently induced proliferation of the relevant T-cell clone in an HLA-restricted manner when adding either intact antigen or antigenic peptides. CONCLUSIONS: BAL cells have the capacity to process and present antigens adequately, irrespective of whether they are derived from healthy individuals or from patients with sarcoidosis, implying the alveolar space as an important location for active immune reactions.

Adult↗

PubMed1997

The defective antigen-presenting activity of murine fetal macrophage cell lines.

We have previously reported that placental macrophages of fetal origin have a decreased ability to present antigen. To clarify the underlying mechanism for this deficiency, we have generated primary fetal macrophage cell lines. Our data show that despite their defective antigen-presenting ability, fetal macrophages do express all known accessory molecules, intracellular adhesion molecule-1, B7 and major histocompatibility complex class II molecules. However, fetal macrophages do not express detectable invariant chain mRNA which is known to have a major role in the class II-associated antigen-processing pathway. Since fetal macrophages can neither present antigenic peptides nor superantigen, the diminished invariant chain expression alone cannot account for the impaired antigen-presenting function of fetal macrophages.

Animals↗

PubMed2003

Repetitive versus monomeric antigen presentation: direct visualization of antibody affinity and specificity.

The concept of presenting antigens in a repetitive array to obtain high titers of specific antibodies is increasingly applied by using surface-engineered viruses or bacterial envelopes as novel vaccines. A case for this concept was made 25 years ago, when producing high-titer antisera against ordered arrays of gp23, the major capsid protein of bacteriophage T4 (Aebi et al., Proc. Natl. Acad. Sci. USA, 74 (1977) 5514-5518). In view of the current interest in this concept we thought it useful to employ this system to directly visualize the dependence of antibody affinity and specificity on antigen presentation. We compared antibodies raised against T4 polyheads, a tubular variant of the bacteriophage T4 capsid, which have gp23 hexamers arranged in a crystalline lattice (gp23(repetitive)), with those raised against the hexameric gp23 subunits (gp23(monomeric)). The labeling patterns of Fab-fragments prepared from these antibodies when bound to polyheads were determined by electron microscopy and image enhancement. Anti-gp23(repetitive) bound in a monospecific, stoichiometric fashion to the gp23 units constituting the polyhead surface. In contrast, anti-gp23(monomeric) decorated the polyhead surface randomly and with a 40-fold lower occupancy. These results concur with the difference in titers established by ELISA for the antisera against the repetitively displayed form of antigen (anti-gp23(repetitive)) and the randomly presented antigen (gp23(monomeric)), and they constitute a compelling visual documentation of the concept of repetitive antigen presentation to elicite a serotype-like immune response.

Animals↗

PubMed2005

Direct processing and presentation of antigen from malaria sporozoites by professional antigen-presenting cells in the induction of CD8 T-cell responses.

Irradiated malaria sporozoites induce better protection than viable untreated sporozoites. We observed early differences between irradiated and viable untreated sporozoites in priming responses in vivo to a protective CD8 T-cell epitope, pb9, of the circumsporozoite protein of Plasmodium berghei. Sporozoites were processed for MHC class I presentation by dendritic cells (DC) to prime pb9-specific IFN-gamma-producing CD8 T cells. DC pulsed with untreated and irradiated sporozoites were similarly capable of priming central memory T-cell responses, detectable by the IFN-gamma cultured ELISPOT assay. However, irradiation significantly enhanced sporozoites' ability to prime effector T-cell responses detectable by the IFN-gammaex vivo ELISPOT assay. Irradiation also enhanced the ability of splenic APC to process and present sporozoites in order to re-stimulate pb9-specific polyclonal and clonal T-cell responses. Sporozoites did not stimulate T cells in the absence of APC. Over-irradiation decreased the sporozoites' T-cell stimulating capacity in vitro at high parasite doses, which may indicate that an optimal irradiation dose is necessary to induce protective immunity by sporozoite inoculation. The induction of sporozoite-specific CD8 T-cell responses without the need for liver stage infection identifies a potentially important mechanism in the development of pre-erythrocytic immunity.

Animals↗

PubMed2002

Germinal center B cells regulate their capability to present antigen by modulation of HLA-DO.

Peptide acquisition by MHC class II molecules is catalyzed by HLA-DM (DM). In B cells, HLA-DO (DO) inhibits or modifies the peptide exchange activity of DM. We show here that DO protein levels are modulated during B cell differentiation. Remarkably, germinal center (GC) B cells, which have low levels of DO relative to naive and memory B cells, are shown to have enhanced antigen presentation capabilities. DM protein levels also were somewhat reduced in GC B cells; however, the ratio of DM to DO in GC B cells was substantially increased, resulting in more free DM in GC B cells. We conclude that modulation of DM and DO in distinct stages of B cell differentiation represents a mechanism by which B cells regulate their capacity to function as antigen-presenting cells. Efficient antigen presentation in GC B cells would promote GC B cell-T cell interactions that are essential for B cells to survive positive selection in the GC.

Antigen Presentation↗

PubMed2005

Antigen presenting cells (APCs) from thermally injured and/or septic rats modulate CD4+ T cell responses of naive rat.

Regulation of immune response is marked by complex interactions among the cells that recognize and present antigens. Antigen presenting cells (APCs), the antigen presenting cell component of the innate immune response plays an important role in effector CD4+ T cell response. Thermal injury and/or superimposed sepsis in rats' leads to suppressed CD4+ T cell functions. We investigated modulations of CD4+ T cell function by APCs (purified non-T cells) from thermally injured and/or septic rats. Rats were subjected to 30% total body surface area scald burn or exposed to 37 degrees C water (Sham burn) and sepsis was induced by cecal-ligation and puncture (CLP) method. At day 3 post-injury animals were sacrificed and CD4+ T cells and APCs from mesenteric lymph nodes (MLN) were obtained using magnetic microbead isolation procedure. APCs from injured rats were co-cultured with sham rat MLN CD4+ T cells and proliferative responses (thymidine incorporation), phenotypic changes (Flow cytometry), IL-2 production (ELISA) and CTLA-4 mRNA (RT-PCR) were determined in naive rat CD4+ T cells. The data indicate that APCs from thermally injured and/or septic rats when co-cultured with CD4+ T cells suppressed CD4+ T cell effector functions. This lack of CD4+ T cell activation was accompanied with altered co-stimulatory molecules, i.e., CD28 and/or CTLA-4 (CD152). In conclusion, our studies indicated that defective APCs from thermally injured and/or septic rats modulate CD4+ T cell functions via changes in co-stimulatory molecules expressed on naive CD4+ T cells. This altered APC: CD4+ T cell interaction leads to suppressed CD4+ T cell activation of healthy animals.

Animals↗

PubMed1994

Modulation of antigen-presenting capacity of human monocytes by HIV-1 GP120 molecule fragments.

The two fragments of HIV-1 gp120 molecule were synthesized to study their interaction with human monocytes. Previous observations indicated that recombinant gp120 fragment (aa residues 410-511) encompassing CD4 binding region (rp120cd) induced tumour necrosis factor alpha (TNF) production in monocytes, while a similar fragment (rp120) not containing the CD4 binding sequence (aa 446-511) was inactive. This paper shows that rp120cd depressed monocyte ability to present antigen (PPD) to autologous T lymphocytes while rp120 was noninhibitory. The rp120cd interacted with monocytes but not T lymphocytes. Anti-TNF receptor type A antibody (utr-1) prevented the depression of antigen presentation caused by rp120cd, which suggested a role for TNF and its receptor. The depression of antigen presentation was seen only when monocytes were treated with rp120cd before, but not after, pulse with antigen. Parallel changes were observed in PPD-induced IL-6 production. Thus, induction of TNF by gp120 may be associated with impairment of antigen-presenting capacity of monocytes seen in AIDS patients.

Antigen Presentation↗

PubMed2003

Polyphenolic antioxidants inhibit peptide presentation by antigen-presenting cells.

Antigen-presenting cells (APC) provide two essential signals, e.g., antigenic peptides as well as costimulatory molecules for T-cell activation. Small molecules of smoke tobacco extracts (SM-STE) inhibited antigen presentation of A20 to OVAp-specific T-cell hybridomas. Pretreatment of A20 but not T hybridomas abrogates the APC function. Viability of APC and levels of MHCII, CD40 and B7 of APC were not affected by this treatment. The active principle, inhibiting APC was reproduced with pure tobacco polyphenols, quercetin and its glycoside, rutin. Antioxidant activity of rutin is relevant since rutin downregulated levels of reactive oxygen species (ROS) in phorbol ester-stimulated A20; moreover, another antioxidant, N-acetyl cysteine (NAC) also inhibited antigen presentation, albeit at a higher concentration. Other types of APC, such as bone marrow-derived mast cells (BMMC), MHCII-transfected fibroblast, and splenocytes are affected by tobacco polyphenols. We propose that polyphenols may affect redox-sensitive signal transduction pathway since APC function of PD 98059, MEK inhibitor-pretreated A20 were similarly abrogated. Taken together, we propose that maintaining appropriate intracellular redox of APC is crucial for its antigen-presenting function.

Acetylcysteine↗

PubMed1994

HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells.

Major histocompatibility complex (MHC) class II molecules are highly polymorphic cell-surface glycoproteins that present antigenic peptides to CD4+ T lymphocytes. The normal assembly of class II molecules with cognate peptides for antigen presentation requires an accessory function provided by a gene mapping to the class II region of the HLA complex. The isolation of somatic cell mutants of antigen-presenting cells (APC) has shown that at least one gene which maps between HLA-DP and HLA-DQ, provisionally designated c2p-1 (ref. 3), mediates this process. Here we describe a unique new mutant 2.2.93, which manifests defective formation of class II/peptide complexes like that described in c2p-1 mutants. We show that (1) mutant 2.2.93 contains a mutation in HLA-DMA, and a representative c2p-1 mutant, 9.5.3, contains a mutation in HLA-DMB; and (2) transfection and expression of DMA complementary DNA in 2.2.93, and DMB cDNA in 9.5.3, reverses their mutant phenotypes. These results show that HLA-DMA and -DMB, genes of previously unknown function mapping between HLA-DP and HLA-DQ, are required for the normal assembly of peptides with MHC class II molecules. They suggest that HLA-DMA and -DMB encode subunits of a functional heterodimer which is critical in the pathway of class II antigen presentation.

Antigen-Presenting Cells↗

PubMed1989

Antigen presentation in brain: brain endothelial cells are poor stimulators of T-cell proliferation.

The capacity of rat brain capillary endothelium to present antigen to primed peripheral lymph node cells or to ovalbumin-specific T-cell lines was examined in vitro. Brain endothelium can present antigen, but it is generally ineffective at stimulating T-cell division. Division is only seen when indomethacin is included in the cultures to suppress eicosanoid production. Even under these conditions an endothelial monolayer is only 1/40 as effective as a thymocyte monolayer in stimulating division. The failure to act as an effective antigen presenting tissue is not due to lack of IL-1 production, nor is it related to the extended time required to induce MHC class II molecules on these cells. In the presence of high levels of antigen-specific T cells, the endothelium appears to be subject to cytotoxic damage, so that T-cell stimulation is lowest with higher numbers of T cells--the opposite of that seen with conventional antigen-presenting cells. These findings support the view that brain endothelial cells are not important in stimulating T-cell division during the development of immune reactions in brain, although these cells may be recognizable by class II-restricted cytotoxic cells.

Animals↗

PubMed2002

The capacity of noninflammatory (steady-state) dendritic cells to present antigen in the primary response is preserved in acutely protein- or energy-deficient weanling mice.

The objective of this investigation was to determine the influence of wasting protein and/or energy deficits on the capacity of dendritic cells to initiate primary responses. Weanling male and female C57BL/6J mice were permitted free access to a complete purified diet, free access to an isocaloric low protein purified diet (combined deficiencies of protein and energy) or restricted intake of the complete diet (energy deficiency) for up to 14 d; a 19-d-old zero-time control group was also included. Malnourished mice lost 1.5-2% of initial body weight daily. Antigen presentation by dendritic cells from spleen and lymph nodes was assessed in vitro by the primary one-way allogeneic mixed lymphocyte reaction using CBA/J mononuclear or CD4(+) T cells as responders. This function was sustained despite advanced weight loss and, remarkably, was increased in cell suspensions from 14-d energy-deficient mice. Antigen presentation by dendritic cells in mononuclear suspensions was examined in vivo using the host-vs.-graft response in CBA/J recipients, and an ontogeny-related increase was sustained in both malnourished groups through 14 d of weight loss. Neither wasting protocol influenced the proportion of mononuclear cells (1-2%) exhibiting dendritic cell phenotype (CD11c(+)F4/80(-/low)) in the cellular suspensions used to study antigen-presenting activity. Consequently, these functional studies are interpretable on a per dendritic cell basis. In the absence of infectious or inflammatory pressure, the dendritic cell retains antigen-presenting capacity despite acute (wasting) deficiencies of protein and/or energy. The results are relevant to presentation of both foreign (adjuvant role) and self (tolerizing role) antigens by the dendritic cell.

Acute Disease↗

PubMed1996

Localization of DNA damage and its role in altered antigen-presenting cell function in ultraviolet-irradiated mice.

Prior ultraviolet (UV) irradiation of the site of application of hapten on murine skin reduces contact sensitization, impairs the ability of dendritic cells in the draining lymph nodes (DLN) to present antigen, and leads to development of hapten-specific suppressor T lymphocytes. We tested the hypothesis that UV-induced DNA damage plays a role in the impaired antigen-presenting activity of DLN cells. First, we assessed the location and persistence of cells containing DNA damage. A monoclonal antibody specific for cyclobutyl pyrimidine dimers (CPD) was used to identify UV-damaged cells in the skin and DLN of C3H mice exposed to UV radiation. Cells containing CPD were present in the epidermis, dermis, and DLN and persisted, particularly in the dermis, for at least 4 d after UV irradiation. When fluorescein isothiocyanate (FITC) was applied to UV-exposed skin, the DLN contained cells that were Ia+, FITC+, and CPD+; such cells from mice sensitized 3 d after UV irradiation exhibited reduced antigen-presenting function in vivo. We then assessed the role of DNA damage in UV-induced modulation of antigen-presenting cell (APC) function by using a novel method of increasing DNA repair in mouse skin in vivo. Liposomes containing T4 endonuclease V (T4N5) were applied to the site of UV exposure immediately after irradiation. This treatment prevented the impairment in APC function and reduced the number of CPD+ cells in the DLN of UV-irradiated mice. Treatment of unirradiated skin with T4N5 in liposomes or treatment of UV-irradiated skin with liposomes containing heat-inactivated T4N5 did not restore immune function. These studies demonstrate that cutaneous immune cells sustain DNA damage in vivo that persists for several days, and that FITC sensitization causes the migration of these to the DLN, which exhibits impaired APC function. Further, they support the hypothesis that DNA damage is an essential initiator of one or more of the steps involved in impaired APC function after UV irradiation.

Animals↗

PubMed1994

Truncation of the A alpha chain of MHC class II molecules results in inefficient antigen presentation to antigen-specific T cells.

Antigen presenting cells (APC) expressing MHC class II molecules composed of chains with part or all of the cytoplasmic domains deleted are inefficient at presenting hen egg lysozyme peptides to antigen specific T cell hybrids compared with APC that express wild-type MHC class II molecules. This effect is most apparent for mutants in which the alpha chain has been truncated. The inefficiency in antigen presentation can be amplified by pulsing the APC for 4 h with peptide rather than having peptide present throughout the presentation assay. Fixation of antigen-pulsed APC improves the capacity of APC with truncated class II molecules to stimulate T cell hybrids. Fixation of APC prior to exposure to antigen also leads to significant improvement in antigen presentation by the truncated class II molecules. Because the inefficiency of a given hybrid for antigen presentation does not correlate with its ability to transduce a signal as measured by protein kinase C translocation, we suggest that defects in this pathway are not the only cause of impaired antigen presentation. However, because previous studies have demonstrated the need for an intact cytoskeleton for successful antigen presentation, we propose that the carboxy truncated class II molecules are inefficient in antigen presentation because they are unable to generate the signal that ultimately leads to their interaction with the cytoskeleton. These observations underscore the complexity of the events that are required for achieving effective interactions between MHC class II molecules and TCR, and suggest, with regard to efficient antigen presentation, that the physical state of the class II molecules is at least as important as their signal transducing capacity.

Animals↗

PubMed1982

Ia antigen expression and antigen-presenting function by macrophages isolated from hypersensitivity granulomas.

Macrophages were isolated from granulomas elicited in the liver by the eggs of the trematode Schistosoma mansoni. They were analyzed for the expression of determinants encoded by the I-A subregion of the major histocompatibility complex and for their ability to present antigen in a T cell proliferation assay. Seventy-five to 81% of the macrophages were found to bear I-A antigens after 24 hr in culture; they also were shown to be effective in carrying out antigen-presenting function. Subsequent in vitro cultivation for up to 4 days demonstrated a progressive loss of I-A molecules, which correlated with a corresponding reduction in antigen-presenting capability. The latter was antigen-specific, blocked by monoclonal antibody directed against I-A, and abrogated after depletion of I-A-positive macrophages. Populations of macrophages from hepatic egg granulomas were richer in I-A-positive cells, and were more effective in terms of antigen-presenting capability compared to those obtained from foreign body-type granulomas. These observations suggest a central role for macrophages from infectious granulomas in the induction and maintenance of immunity and hypersensitivity.

Animals↗

PubMed1990

Beta 2-microglobulin restriction of antigen presentation.

Antigens are generally thought to be recognized by cytotoxic T lymphocytes as peptides in the context of class I major histocompatibility proteins complex, which are heterodimers of heavy chains noncovalently associated with beta 2-microglobulin (beta 2m). The highly polymorphic nature of the heavy chains and their resulting ability to present different sets of peptides has presumably evolved to allow potent immune responses against most pathogens. By contrast, the polymorphism of beta 2m is limited; seven alleles are known in the mouse and only one has been identified in humans. beta 2-Microglobulin was consequently thought to have only structural functions: namely, to ensure correct folding of class I molecules and their transport to the cell surface. Although beta 2m is not implicated directly in the formation of the peptide binding site, we report here that it participates in the selection of MHC class I molecule-associated peptides.

Amino Acid Sequence↗

PubMed1995

Genetic control of immunity to Heligmosomoides polygyrus: fixed H-2 E positive but not H-2 negative cells can present antigen to a parasite-specific T cell hybridoma.

A number of T cell hybridomas were produced to adult worm homogenate (AWH) antigen of the nematode parasite Heligmosomoides polygyrus. All of the hybridomas were of the H-2d haplotype and could potentially accept antigen in the context of either the Ad or Ed, H-2 molecules. Three types of antigen presentation were observed, with some of the T cell hybridomas accepting antigen in the context of the E and some in the context of the A molecule. A third type of hybridoma responded to antigen presented by paraformaldehyde fixed APC, but only when APCs were E positive. These same hybridomas, were however, stimulated by AWH, when the antigen was presented by syngeneic but unfixed, E positive or E negative APC. Therefore these data indicate that certain H. polygyrus-specific T cell hybridomas can accept parasite antigen when presented in the context of either the H-2 A or E molecule, but the presentation of antigen by the two different MHC Class II molecules, can apparently utilize differing processing mechanisms.

Animals↗