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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Class II MHC molecules on the surface of an APC present immunogenic peptides derived mainly from exogenous proteins to CD4+ T cells. During its transport to the cell surface, class II molecules intersect the endocytic pathway where they acquire peptides derived from endocytosed proteins. However, class II-restricted presentation of endogenously derived peptides can also occur. The current studies were undertaken to examine the ability of different types of APC to generate and present four different T cell determinants derived from an endogenous, nonsecreted, truncated form of hen-egg white lysozyme (HEL[1-80]-Kk). This was compared with the ability of these APC to generate the same determinants from exogenous HEL. All the peptides derived from endogenous HEL[1-80]-Kk tested, were presented by B cells to HEL-specific T cell hybridomas with an efficiency similar to presentation of the same determinants from exogenous HEL. In contrast, an I-Ak-bearing rat fibroblast was unable to generate the HEL peptide 25-43 from exogenous HEL, but could efficiently produce it from endogenous HEL[1-80]-Kk. The results indicate first, that peptides derived from an endogenous Ag can be presented by MHC class II molecules with an efficiency comparable to that of the presentation of the exogenous Ag. Second, that Ag-presenting B cells can generate the same repertoire of antigenic peptides from endogenous Ag as those generated from the exogenous protein. And third, that in contrast to B cells, certain "nonprofessional" APC can generate, from an endogenous protein, T cell determinants distinct from those generated after endocytosis of the exogenous protein. These results suggest that processing of exogenous and endogenous Ag by different APC take place in different intracellular compartments.
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PMID:Processing of an endogenous protein can generate MHC class II-restricted T cell determinants distinct from those derived from exogenous antigen. 165 43

There is controversy regarding the ability of short term (2 to 3 days) cultured epidermal Langerhans cells (cLC) to process and present intact protein Ag to primed T cells. Some studies have shown that cLC are potent APC for both haptens and intact protein Ag, whereas in others cLC have been unable to process and present intact protein Ag. In an attempt to resolve this controversy, we tested the ability of Langerhans cells from several strains of mice to process and present intact protein Ag to T cell clones and T cell hybridomas. We found that both cLC and freshly prepared Langerhans cells from various Iak mice, including BALB.k mice, process and present intact protein antigens (i.e., hen egg lysozyme, cytochrome c, and OVA) to T cells. These functions are retained in cLC cultured for 7 days. In contrast, cLC from Iad mice do not process intact protein Ag, such as hen egg lysozyme and myoglobin, although they can present relevant peptides to specific T cells and are potent stimulators of allogeneic responses. Furthermore, cLC from (Iak x Iad)F1 mice process and present intact protein Ag to Iak-restricted T cells, but not to Iad-restricted T cells. Although cLC that processed and presented intact protein Ag to T cells exhibited enhanced class II MHC expression, they were, on a per cell basis, somewhat less efficient than were fresh Langerhans cells. Finally, we found that if Iad Langerhans cells are pulsed with intact protein Ag and then cultured for 3 days, they are then fully capable of inducing Ag- and MHC-specific T cell proliferation.
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PMID:The ability of cultured Langerhans cells to process and present protein antigens is MHC-dependent. 184 34

Helper (CD4+) T lymphocytes recognize protein Ag as peptides associated to MHC class II molecules. The polymorphism of class II alpha- and beta-chains has a major influence on the nature of the peptides presented to CD4+ T lymphocytes. For instance, T cell responses in H-2k and H-2b mice are directed at different epitopes of the hen egg lysozyme (HEL) molecule. The current studies were undertaken with the aim of defining the role of mixed haplotype I-A (alpha k beta b and alpha b beta k) molecules in T cell responses to HEL in (H-2k x H-2b)F1 mice, as well as the nature of the immunogenic peptides of HEL recognized in the context of I-A alpha k beta b and I-A alpha b beta k. A series of HEL-reactive T cell lines and hybridomas derived from MHC class II heterozygous (C57BL/6 x C3H F1) mice were established. Their responsiveness to HEL and synthetic HEL peptides was analyzed with the use of L cells transfected with either I-A alpha k beta b or I-A alpha b beta k as APC. Out of 28 clonal T cell hybridomas tested, 13 (46%) only responded to HEL presented by I-A alpha k beta b, 11 (40%) by I-A alpha b beta k (and to a minor extent I-A alpha k beta k), only 4 (14%) were primarily restricted by I-Ak, and none by I-Ab. All the I-A alpha k beta b-restricted T cell hybridomas responded to the HEL peptide 46-61 and to its shorter fragment 52-61, even at concentrations as low as 0.3 nM. As this determinant has been previously defined as immunodominant for I-Ak but not for I-Ab mice, these results suggest a role for the I-A alpha k chain in the selection and immunodominance of HEL 52-61 in H-2k mice. The fine specificity of I-A alpha k beta b-restricted T cell hybridomas for a series of different HEL peptides around the sequence 52 to 61 suggests that peptide 52-61 binds to I-A alpha k beta b with higher affinity than to I-A alpha k beta k. The peptides recognized in the context of I-A alpha b beta k and I-A alpha k beta k were not identified.
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PMID:Co-dominant restriction by a mixed-haplotype I-A molecule (alpha k beta b) for the lysozyme peptide 52-61 in H-2k x H-2b F1 mice. 197 Mar 51

We have analyzed the stability of Ag-class II complexes on the surface of live APC. It was found that the disappearance of complexes formed by I-Ed and the hen egg lysozyme 107-116 peptide is twice as rapid on the surface of live, as compared to glutaraldehyde-fixed APC. Moreover, the addition of peptides with a high affinity for I-Ed could reduce the half-life of Ag-class II complexes on either live or fixed APC. The same effect was detectable using purified class II molecules adhered on plastic microtiter wells, and even in the case of complexes formed in vitro between radiolabeled Ag and purified class II molecules. This effect of accelerated dissociation appeared to be specific because only I-Ed binding peptides were able to accelerate the dissociation of the hen egg lysozyme 107-116/I-Ed complex either on the surface of cells or in purified form in solution, and high affinity I-Ed binders did not affect the half-life of purified OVA 323-339/I-Ad complexes. These results demonstrate that free ligand can influence the kinetics of dissociation of class II-peptide complexes, and therefore suggest that a mechanism other than the classical first order kinetics may be involved in this process.
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PMID:Free ligand-induced dissociation of MHC-antigen complexes. 202 78

The binding of protein antigens to APC with heterocrosslinked bispecific antibodies (HBAs) enhances their processing and presentation to Th cells in vitro. Here we have asked whether HBAs could also increase immune responses in vivo. We immunized mice with hen egg lysozyme (HEL) in the presence or absence of HBA, and followed antibody production after the primary challenge and after a secondary boost. We found that HBAs that bind antigen to MHC class I or II molecules, to Fc gamma R, but not to surface IgD, enhance the immunogenicity of HEL. HBAs that bound HEL to MHC class II molecules, for examples, decreased the amount of antigen required to elicit a primary anti-HEL antibody response in mice by 300-fold, and the amount required to prime for a secondary response by 10(3)- to 10(4)-fold. In fact, HBAs were as effective as IFA in generating antibody responses. Since adjuvants cannot be used in humans, HBAs could prove useful for immunizing people, especially in cases where, due to scarcity or toxicity, minute doses of antigen must be used.
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PMID:Enhanced antigen immunogenicity induced by bispecific antibodies. 235 31

The presentation of protein Ag with MHC class II proteins involves the uptake of the protein Ag by endocytosis followed by processing, probably proteolysis, in an intracellular acidic compartment. However, there remains considerable controversy as to the precise route taken by the antigen and the MHC class II protein during this process. The unusual stability of Ag-MHC class II protein complexes has led to speculation that antigen can only associate with newly synthesized MHC class II molecules. An alternate possibility is that the MHC class II binding site can be regenerated within the cell during internalization and recycling of MHC class II proteins. To address these possibilities, three different murine B lymphoma lines were tested for their ability to process and present native protein Ag in the presence of the protein synthesis inhibitor cycloheximide or the protein synthesis inhibitor cycloheximide or the protein export inhibitor, Brefeldin A. Both agents blocked the presentation of native OVA or native hen egg lysozyme to Ag-specific T cell hybridomas. No effect was seen on peptide presentation or on presentation to allo- or autoreactive T cells. Inasmuch as Brefeldin A has been previously shown to block protein export without affecting protein internalization or protein degradation in the endocytic pathway, the simplest interpretation of these data is that antigenic fragments generated in the APC after uptake by the endocytic pathway, preferentially associate with newly synthesized rather than mature MHC class II proteins.
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PMID:MHC class II-restricted presentation of native protein antigen by B cells is inhibitable by cycloheximide and brefeldin A. 237 60

We have studied the relationship between MHC-restricted, Ag-specific recognition and TCR structure in a panel of seven Th-hybridomas specific for the foreign protein Ag, hen egg-white lysozyme, and the I-Ak class II MHC molecule. The fine specificity of these Th cells had been determined previously by their reactivity to a panel of APC lines bearing mutant I-Ak molecules and to proteolytic fragments of HEL. TCR gene segment composition was determined by cDNA cloning and DNA sequencing. A heterogeneous, yet repetitive usage of gene segments was observed within the panel. The same V alpha C10-J alpha MD13 rearrangement was used in three of the hybridomas, two with identical Ag and MHC-restriction fine specificities. The prevalent usage of the V beta 14 gene segment and members of J beta 2 cluster was noted. Inasmuch as gene segment usage did not correlate with MHC-restriction or Ag fine specificity alone, these results favor an interactive Ag model of T-cell recognition, in which Ag and MHC are recognized as a bimolecular complex.
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PMID:T cell receptor gene segment usage in a panel of hen-egg white lysozyme specific, I-Ak-restricted T helper hybridomas. 246 15

Bispecific heteroconjugate antibodies can bind soluble protein Ag to APC and thereby enhance Ag presentation. We used such antibodies to bind hen egg lysozyme (HEL) to various structures on the surface of normal splenic B cells to determine which structures would provide the best targets for enhanced presentation. We found that HEL was presented efficiently to hybridoma T cells if bound to sIgD, sIgM, or class I or II MHC molecules, but not at all if bound to Fc gamma RII, or B220 molecules on B cells. The efficiency of presentation of HEL was measured as a function of the amount of 125I-HEL bound per cell. HEL was presented with 5 to 10 times greater efficiency when bound to sIg, than when bound to MHC molecules. When compared on the basis of the amount of HEL bound, sIgD and sIgM functioned equally as target structures, as did class I and class II MHC molecules. Large amounts of HEL bound to B220, but no presentation resulted, indicating that focusing HEL to the APC surface was not sufficient for presentation to occur. HEL was internalized rapidly and in large amounts when bound to sIgD or sIgM, but slowly and in small amounts, when bound to class I or class II MHC molecules. Thus, a rapid rate of internalization may in part explain the high efficiency of Ag presentation after binding to sIg. However, the small amount of HEL internalized via MHC molecules was utilized efficiently for presentation. These results indicate that sIgM and sIgD serve equally on normal B cells to focus and internalize Ag and enhance Ag presentation, but that class I or class II MHC molecules can also be used to internalize Ag and enhance Ag presentation, perhaps by a separate intracellular processing pathway.
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PMID:Efficiency of antigen presentation after antigen targeting to surface IgD, IgM, MHC, Fc gamma RII, and B220 molecules on murine splenic B cells. 247 43

To study the biochemistry of processing of a soluble protein Ag by an APC, we investigated how 125I-labeled human insulin (HI) is processed in situ by TA3 mouse hybridoma B cells. Fractionation of TA3 cells into their extracellular, plasma membrane-associated and intracellular compartments coupled with the use of HPLC enabled us to analyze several peptides derived from each compartment. One HI peptide found in all three compartments is composed of residues A1-A14 disulfide-linked to B7-B26 (A1-A14/B7-B26). The presence of this peptide in the extracellular compartment likely resulted from digestion of HI by an enzyme(s) released from the APC. Extracellular processing of radiolabeled HI was inhibited completely by unlabeled HI and N-ethylmaleimide, an inhibitor of a previously described insulin-specific protease, partially by lysozyme but not by BSA or OVA. This suggests that the enzyme involved in the extracellular processing of insulin is relatively insulin-specific and gives rise to the A1-A14/B7-B26 peptide. The processing of HI both at the plasma membrane and intracellularly was inhibited by chloroquine, monensin, and NH4Cl, suggesting that both intracellular pH changes and endocytic and exocytic events may be required for these compartments to process insulin. Kinetic analyses revealed that the processing of insulin into the A1-A14/B7-B26 peptide is first detected at the plasma membrane then intracellularly and finally in the extracellular compartment. This unlabeled A1-A14/B7-B26 peptide was purified from the extracellular compartment of TA3 APC by HPLC; when presented by TA3 APC this peptide effectively stimulated pork insulin (PI/I-Ad) specific Th cells to secrete IL-2. These data, taken together with the identification of another processed insulin peptide, A7-A11/B7-B26, have enabled us to elucidate the first steps in the biochemical pathway(s) of processing of insulin as an Ag in a B cell APC.
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PMID:Processing and presentation of insulin. II. Evidence for intracellular, plasma membrane-associated and extracellular degradation of human insulin by antigen-presenting B cells. 265 61

Synthetic peptides corresponding to sequences 46-62 and 51-62 of mouse lysozyme and 46-61 of hen egg-white lysozyme (HEL) were used as competitors in a variety of T cell responses. The competitors, according to their binding specificity for major histocompatibility complex (MHC) were expected to inhibit T cell responses restricted to I-Ak, but not those restricted to I-Ad, I-Ek molecules. In competition experiments with T cell hybridomas, the poor binder I-Ed molecule required 10- to 15-fold higher competitor concentrations than the good binder I-Ak molecule to achieve 50% inhibition of antigen presentation. Similarly, the nonresponder state of H-2d mice to HEL peptide 46-61 could be overcome by increasing the immunizing dose, and proliferative T cell responses to different antigens in association with a variety of class II MHC molecules could be blocked by the mouse lysozyme and HEL peptides. Thus, the capability of some and failure of other MHC molecules to bind certain peptides appeared quantitative, rather than of an all or none nature, in these experimental systems. The susceptibility of uncloned T cell lines to peptide competitors was found to decrease with time. Lines maintained by repeated restimulation with antigen and APC, but without exogenous interleukin 2, acquired resistance within weeks. In contrast, T cell clones retained their susceptibility to peptide competitors over a long period of time. The latter data raise the possibility that a competition between ubiquitous (self) peptides and foreign antigen may result in the selection of T cells that have high avidity for the activating antigen-MHC complex, and are thus relatively resistant to competition at the level of antigen presentation.
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PMID:Inhibition of T cell response with peptides is influenced by both peptide-binding specificity of major histocompatibility complex molecules and susceptibility of T cells to blocking. 278 51


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