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

Organ graft rejection is caused by the recognition of allogeneic MHC molecules by recipient T cells by two different pathways. The indirect pathway of alloreactivity requires the presentation of MHC peptides from the graft by autologous APC, as with conventional antigen. The direct pathway, on the other hand, requires the recognition of foreign MHC on foreign cells. The regulatory mechanisms for this component of alloreactivity have not been extensively studied. We show here that the T cell response activated by alloantigens in the direct pathway is similarly constrained and modulated by cytokines, as has been shown for classic antigen presentation. Thus, the inclusion of IL-2 or TGF-beta in MLC performed with purified responder T cells resulted in outgrowth of cells secreting IL-2 and IFN-gamma, whereas addition of IL-4, IL-10, or anti-TGF-beta encouraged outgrowth of cells secreting IL-4 and IL-10. T cells alloactivated via the direct pathway and then cloned in IL-2 alone secreted IL-4 and IL-10 as well as IFN-gamma and IL-2 (Th0 phenotype). Established clones remained susceptible to cytokine modulation, such that IL-4 and IL-10 decreased their secretion of IL-2 and IFN-gamma, whereas TGF-beta suppressed IL-4 and IL-10 secretion. The first alterations of Th0 toward Th1 or Th2 phenotypes could already be observed after only a very brief exposure to cytokines of 48 hr, followed by extended culture with IL-2 alone. These results confirm that human T cells with Th1 and Th2 phenotypes, recognizing alloantigen via the direct pathway, derive from the same IL-2-secreting precursor and can be manipulated by cytokines in an analogous fashion to conventional antigen-reactive cells. These findings may have implications for manipulating the direct pathway of alloantigen recognition in human organ transplantation.
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PMID:Cytokine modulation of TH1/TH2 phenotype differentiation in directly alloresponsive CD4+ human T cells. 890 Mar 9

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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PMID:Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. 892 Aug 82

When examining the effects of analogue peptides on changes in response patterns of a human Th0 clone DT13.2 that recognizes a peptide fragment (18RSLRTVTPIRMQGG31) derived from a group I allergen in Dermatophagoides farinae in the context of HLA-DQ6 (DQA1*0102/DQB1*0602), we found that replacement of the 21st residue Arg to Lys resulted in a significant increase in IFN-gamma production, with no remarkable changes either in proliferative response or IL-4 production, at high doses of the peptide. Selective enhancement of IFN-gamma production by the analogue peptide was accompanied by an increased production of IL-12, which was suppressed by an anti-IL-12 Ab down to the level of IFN-gamma production induced by the wild-type peptide. On the contrary, co-incubation with neutralizing Abs to IFN-gamma and IFN-gamma receptor did not affect IL-12 production, indicating that increased production of IL-12 stimulated by the analogue peptide was not due to an effect of IFN-gamma from T cells. Peptide-induced up-regulation of CD40 ligand expression at high peptide concentrations showed no difference between the wild-type and analogue peptides. These data collectively indicate that certain T cell/APC interactions mediated through TCR and altered TCR ligands affect APC responses and that signals transmitted to APC are as indispensable as those to T cells in determining T cell response patterns.
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PMID:Altered TCR ligands affect antigen-presenting cell responses: up-regulation of IL-12 by an analogue peptide. 894 86

It has long been known that mucosal responses are most effectively stimulated by local presentation of antigen but the mechanisms whereby the gut immune system is able to distinguish between potential pathogens and harmless dietary antigens are not clear. The gut immune system is capable of mounting both primary and secondary responses to potentially harmful antigens while avoiding the expression of damaging responses to harmless food proteins. Historically, most attention has focused on Peyer's patches and there is evidence of their role in the induction of both primary and secondary responses. Fed antigen can also be detected in the intestinal lamina propria (LP) and it has been shown that murine LP cells can stimulate allogenic mixed lymphocyte responses and present KLH to naive T cells. In contrast to guinea pigs, rodents and humans, pig intestinal epithelial cells do not express MHC Class II molecules, but they are present on a number of other cell types in the subepithelial LP. Amongst these are a significant proportion of non-professional APC including endothelial cells and eosinophils. Phenotypically pig LP T cells are a homogeneous population and the majority of CD4 T cells express the low molecular weight isoform of CD45. This is compatible with the suggestion that they are CD45RO-positive cells. A significant proportion of LP CD4 T cells are CD25 (IL-2R) positive, but following activation they secrete IL-4, with little or no IL-2 production. Based upon these observations, we would conclude that the lamina propria is a unique immunological microenvironment, and suggest that it may be of significance not only in surveillance and the provision of help during rapid responses to recall antigens but also in the down-regulation of local responses to food-derived peptides.
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PMID:Antigen presenting cells in the porcine gut. 898 62

Previous studies on human Th subset development were restricted to the analysis of naive T cells activated with anti-CD3 mAb in the absence of physiologic APC. In this study, we have analyzed the role of cytokines and physiologic APC on T cell maturation in an Ag-specific system, in which naive neonatal CD4 T cells were primed with allogeneic dendritic cells (DC). We found that the cytokine profile of primed cells was dependent upon 1) the ratio between T cells and allogeneic DC and 2) the endogenous production of IL-4 and IL-12. Neutralization of IL-4 during primary MLR increased IFN-gamma production at priming and shifted the phenotype of primed cells from Th0 to Th1. These effects were IL-12 dependent, in that they were suppressed by anti-IL-12 Abs. The production of IL-12 in primary MLR was further evidenced by the presence of IL-12 p40 in the culture supernatant fluids. IL-12 production was suppressed by exogenous IL-4 and increased by anti-IL-4 blocking mAbs, indicating that endogenous IL-4 down-regulated IL-12 production by DC. Finally, IL-12 was produced as a result of T cell/DC interaction involving the CD40/CD40 ligand and CD28/B7 costimulation pathways, as revealed by the inhibitory effect of anti-CD40 ligand mAb and CTLA-4Ig. These observations suggest that in neutral conditions, Ag presentation by DC results in the coordinate production of naive T cell-derived IL-4 and DC-derived IL-12 that in concert shape the cytokine profile of Th cells.
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PMID:T cell-derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloantigen-primed naive human CD4 T cells. 899 77

We have previously reported the cloning of a novel cytokine, IFN-gamma-inducing factor (IGIF), which shared some biologic activities with IL-12. In this study, we analyzed the effects of murine IGIF on the activation of T cells, and compared the effects with those of IL-12. IGIF alone had no effect on the activation of T cell lines or Th1 clones, while IGIF increased the IFN-gamma production by antigen-stimulated T cell lines, but had no effect on IL-4 or IL-10 production. As reported with IL-12, IGIF served as a costimulatory factor for Th1 clones stimulated with Ag on B cell APC, immobilized anti-CD3, Con A, or IL-2 to augment IFN-gamma production and to induce IL-2R alpha-chain expression and proliferation of the Th1 clones, whereas IGIF had little or no effect on the IL-4 production and proliferation of Th2 clones stimulated with anti-CD3 or Ag. However, IGIF synergized with IL-12 to further augment the IFN-gamma production of the Th1 clones. Even in the presence of saturated amounts of IL-12, IGIF still augmented the IFN-gamma production and proliferation and enhanced the IL-2R alpha-chain expression of the Th1 clones. In contrast with IL-12, IGIF induced IL-2 production by Ag- or anti-CD3-stimulated Th1 clones. These two findings indicate that IGIF and IL-12 are utilizing different signal transduction pathways. We also found that IGIF as well as IL-12 was endogenously released through interaction between Th1 cells and spleen cell APC in the presence of specific Ag, and that it regulated IFN-gamma production. These results further suggest that IGIF may act as an immunoregulatory factor in the immune response.
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PMID:IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. 902 88

We have previously demonstrated that highly polarized CD4+ Th1 cells isolated from Leishmania major-infected mice could be switched to a Th2-like phenotype when cultured for 1 wk in the presence of APC, L. major Ag, and IL-4, suggesting that the reversion of a differentiated Th response could occur at the population level. To investigate the cellular basis for this population switch, CD4+ lymph node cells from Th1-polarized L. major-infected mice were separated into two subsets based on the level of expression of L-selectin (Mel-14), and each subset was stimulated with APC and IL-2 for 1 wk in the presence or the absence of IL-4. Mel-14low T cells contained all of the initial Th1 activity and retained their Th1 phenotype when cultured with IL-4. In contrast, Mel-14high T cells did not produce cytokines upon challenge with L. major Ag, but gave rise to a Th2-like population after culture with IL-4. Thus, the newly induced Th2 population was derived from undifferentiated cells distinct from the Th1 cells present in the starting population. This undifferentiated Th precursors could be induced to develop into either Th1 or Th2 cells and were not recent thymic emigrants as they were present in mice thymectomized before infection. These experiments show that a chronically stimulated and highly polarized Th1 population consisted of both precursor T cells able to differentiate into Th2 cells and cells fully differentiated into Th1 cells that could not be induced to switch their pattern of cytokine production.
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PMID:The mechanism of in vitro T helper cell type 1 to T helper cell type 2 switching in highly polarized Leishmania major-specific T cell populations. 902 90

Tumor cells genetically modified to coexpress certain cytokines (such as IL-7 or IL-4) and B7.1 have increased immunogenicity. Since tumor Ags can be presented either directly by tumor cells or indirectly by host APC (cross-priming), we asked whether B7.1 and IL-7 or IL-4 complemented each other by improving preferentially one or both pathways of Ag presentation. We used TS/A (H-2d) tumor cells and their IL-7, B7, and IL-7/B7 transfectants, and MCA205 (H-2b) tumor cells and their IL-4 and B7 transfectants. beta-galactosidase (beta-gal) was chosen as surrogate tumor Ag. beta-gal has different predominant MHC class I epitopes in H-2d and H-2b mice. Immunization of (H-2b x d)F1 mice with TS/A/beta-gal transfectants showed that both IL-7 and B7.1 and, as control, granulocyte-macrophage CSF augmented cross-priming and rejection of a challenge with MCA205/beta-gal (H-2b). Similarly, immunization with MCA205/beta-gal B7.1 or IL-4 transfectants enhanced cross-priming and rejection of a challenge with TS/A/beta-gal. beta-gal-specific rejection was confirmed by CTL assay. However, direct Ag presentation by tumor cells was enhanced only by B7.1, and not IL-7. For this study, H-2b nu/nu mice reconstituted with F1 lymphocytes were immunized with H-2d TS/A/beta-gal transfectants and challenged with TS/A/beta-gal. In conclusion, indirect Ag presentation was augmented by B7, IL-7, and IL-4, while direct Ag presentation was improved only by B7.
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PMID:Influence of gene-modified (IL-7, IL-4, and B7) tumor cell vaccines on tumor antigen presentation. 905 19

Injection of goat anti-mouse IgD antibody (G alpha M IgD) to mice has been shown to induce polyclonal IgG1 and IgE production by B cells and IL-4 production by goat Ig-specific T cells. Surface IgD crosslinking also activates function of B cells as antigen presenting cells. Although the G alpha M IgD treatment is a well established system for regulation of immune response against antigens that bind to B cell receptor, we found that the G alpha M IgD treatment also influences immune response against irrelevant bacterial antigen. The T cells from the G alpha M IgD-treated Listeria monocytogenes-infected mice showed increased IL-4 production and decreased IFN-gamma and IL-2 production against listerial antigen compared with those from control L. monocytogenes-infected mice. Interestingly, changes were also found in antigen presenting cells in the G alpha M IgD-treated mice. MHC class II expression of both B cells and macrophages decreased significantly in the G alpha M IgD-treated mice, suggesting cytokine induced by G alpha M IgD-treatment may suppress MHC class II expression and modulate APC function in the G alpha M IgD-treated mice. In accordance with the assumption, T cells from the G alpha M IgD-treated mice produced high amount of IL-4 and IL-10 in in vitro culture with goat serum which contain goat Ig. These result suggest that G alpha M IgD treatment may modulate APC function in the G alpha M IgD-treated mice through Th2 type cytokine(s) produced by goat Ig-specific T cells, which results in changes of Th response against irrelevant antigen.
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PMID:Down-regulation of Listeria monocytogenes-specific Th1 cytokine response by treatment of mice with goat antibody to mouse IgD. 906 84

The elicitation of a specific immune response against allergens depends on the recognition of antigenic determinants (epitopes) by specific T and B lymphocytes. In order to determine the relevant epitopes for human T and B cells and their features in the regulation and production of specific IgE and/or IgG antibodies, we have investigated the immune response to bee venom phospholipase A2 (PLA) in allergic and non-allergic subjects. This enzyme represents the major allergen in bee sting allergy. It consists of 134 amino acid residues with a carbohydrate side chain at position 13 and is available as recombinant protein. We have developed PLA-specific T-cell clones from bee sting allergic and non-allergic human subjects. Using a panel of dodecapeptides overlapping in 10 residues and a large set of 18-25 mer overlapping peptides, we detected three epitopes that were recognized by peripheral blood T-cells and T-cell clones. A fourth determinant involved the carbohydrate moiety on Asn13 of PLA. Whereas the CHO-depending epitope seems to be mostly active in allergics, the other three epitopes are equally recognized by peripheral blood mononuclear cells (PBMC) of both allergic and non-allergic individuals. In T-cell clones, the ratio of IL-4/IFN gamma cytokines and the quality of the activating signal depend on the strength of the binding of the MHC-II/Ag/TcR complex between APC and T-cells. The number of antigen-specific APC-T-cell contact sites can be varied in vitro by changing the dose of antigen added to the cell culture. While isotype switch for both IgE and IgG4 requires IL-4, this cytokine suppresses antigen-specific IgG4 production by already switched B-cells. Therefore, IL-4 and IFN gamma display counter-regulatory effects on the production of IgE being responsible for atopic states and IgG4 antibodies which are signs of a normal immune response to allergen and act as protective antibodies. The combination of this counter-regulation of IgE and IgG4 antibodies with the fundamental law of mass action for chemical equilibrium reactions revealed that the antigen concentration governs to a great part the ratio of IL-4/IFN gamma secretion and therefore the formation of IgE and IgG and allergy or protection, together with the equilibrium constant K, which represents immunological individuality and a measure of Ag presentation.
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PMID:Allergen dose dependent cytokine production regulates specific IgE and IgG antibody production. 909 57


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